Treatment of radiation-damaged bone marrow using galactosyl ceramides

ABSTRACT

The present invention relates to a pharmaceutical composition (a marrow cell proliferation accelerator, a radioprotective agent, a therapeutic agent for thrombocytopenia) comprising a compound represented by the following formula (A), and to a therapeutic or prophylactic method (a method for accelerating marrow cell proliferation, a method for protecting human against radiation damage, a method for the treatment of thrombocytopenia) characterized in that an effective amount of a compound represented by the following formula (A) is administered to human: ##STR1## wherein R 2  represents ##STR2## 26) or --(CH 2 ) 7  CH=CH(CH 2 ) 7  CH 3 , and R 1 , is one of the substituents defined by the following (a) to (d): 
     (a) --CH 2  (CH 2 ) y  CH 3 , 
     (b) --CH(OH)(CH 2 ) y  (CH 3 ) 2 , and 
     (c) --CH(OH)(CH 2 ) y  CH(CH 3 ) 2 , and 
     (d) --CH=CH(CH 2 ) y  CH 3   
     (wherein Y is an integer of 5-17).

This is a continuation of application Ser. No. 08/091,979 filed on Jul.15, 1993, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a medicine comprising as an activeingredient a specific α-galactosylceramide, and a therapeutic method.More specifically, the present invention relates to a marrow cellproliferation accelerator having potent therapeutic effects on variousdiseases caused by the damage to marrow cells; a radiation damageprotector which has a life-span-increasing effect on those who have beenexposed to a lethal dose of radiation, and which is effective forprophylaxis and remedy of side effects caused upon radiotherapy; and atherapeutic agent for thrombocytopenia, capable of increasing the numberof blood platelets or inhibiting a reduction in the number of bloodplatelets. Further, the present invention relates to a method of marrowcell proliferation, a method for protecting a human against radiationdamage, and a method for the treatment of thrombocytopenia, comprisingadministering an effective amount of a specific α-galactosylceramide toa human.

2. Related Art

It is known that marrow cells are damaged and their number is decreasedby irradiation with a large dose of radiation, or by administration of alarge amount of chemotherapeutic agent.

Further, it is known that hypoplastic anemia, osteomyelodysplasia andthe like are diseases caused by a functional disorder (including adecrease in the number) or hypofunction of marrow cells. The marrowcells herein refer to those cells which are present in bone marrow, andinclude red blood cells, neutrophiles, eosinophils, basophils,monocytes, lymphocytes, and various cells, such as blood platelets, invarious differentiated stages.

In order to overcome the damage to marrow cells, which is a cause of theabove-described conditions of diseases or diseases, bone marrowtransplantation or administration of various hematopoietic factors hasbeen attempted, and, in addition, the exploration of novelmarrow-cell-proliferating factors is now being made energetically.

As mentioned above, various diseases or conditions of diseases arecaused by the damage to marrow cells. Since a decrease in the number ofmarrow cells is one of the causes of the diseases, there is a highpossibility that a marrow-cell-proliferation-accelerating material canameliorate the above diseases or conditions of diseases.

rays, β-rays and γ-rays emitted from a radioactive substance, orradiations such as artificially produced potent X-rays, proton rays,neutron rays and electron beams. are indispensable for the treatment ordiagnosis of diseases such as cancer. However, when more than apermissible dose of radiation is used, or when normal tissues or organsin the body are irradiated during treatment, the numbers of white bloodcells, red blood cells and the like are decreased as a side effect ofradiation. Therefore, radiotherapy cannot always be conductedcompletely.

Moreover, irradiation with ultraviolet rays, which is a kind ofradiation, also causes various diseases.

Various methods which can prevent such radiation damages and sideeffects thereof have been studied.

For instance, in a chemical protection method using a medicine, amaterial capable of revivifying the immunological function ofimmunocytes which have been inhibited by radiation, for example,cepharanthine or Sonifilan; or an agent for activating respiration ofcell tissues, for example, cytochrome C, Solcoselin or adenine have beenused. In the present situation that the above materials show only aslight effect on preventing the side effects caused by irradiation withradiation.

Further, with respect to radiation damage, a radiation protectorcontaining a processed material of Streptococcus lactis which caneliminate free radicals or active oxygen produced by the ionizing effectof radiation has been proposed (Japanese Laid-Open Patent PublicationNo. 103023/1987). However, this agent cannot be expected to haveexcellent effects such as a life-span-increasing effect on those who areexposed to a lethal dose of radiation.

A method in which a material having a macrobiotic effect on those whoare exposed to a lethal dose of radiation has been proposed recently.For instance, a method using 2-phenyl-1,2-benzoisoserenazol-3(2H)-on(Japanese Laid-Open Patent Publication No. 135718/1989), a method usinga Cimetidine-copper complex (Japanese Laid-Open Patent Publication No.153640/1989), and a method using a nonapeptide which is known as a serumthymic factor (Japanese Laid-Open Patent Publication No. 36126/1990)have been proposed. However, there are continuous demands for moreexcellent radioprotective agents.

Blood platelets are a blood cell component which play an important rolein the mechanism of hemostasis of the organism. Specific symptoms ofthrombocytopenia are hemorrhage and abnormal blood coagulation.

Hereditary thrombocytopenia, idiopathic thrombocytopenic purpura,hypoplastic anemia and the like have been known as thrombocytopenia inwhich the number of blood platelets decreases. However, a clinicalproblem in recent years is thrombocytopenia caused as a side effect of achemotherapeutic agent or radiotherapy used for the treatment of cancer.

All of the chemotherapeutic agents currently used have a potentbone-marrow-suppressive effect, so that administration of such an agentinduces a remarkable decrease in the number of white blood cells orblood platelets. There are therefore many cases where the treatment hasto be suspended because of this side effect. X-rays or γ-rays, which areused in radiotherapy, also adversely act on hemopoietic tissues such asbone marrow and bring about a drastic decrease in the number of whiteblood cells or blood platelets as in the case where the chemotherapeuticagent is administered. For this reason, irradiation with radiation isoften forced to be discontinued.

Platelet transfusion and bone marrow transplantation are known astherapeutic methods which are often used presently for the treatment ofthrombocytopenia caused by the above-described chemotherapy orradiotherapy for cancer.

However, in the case of the above platelet transfusion, it is necessaryto conduct transfusion frequently because the life span of white bloodcells or blood platelets is short. In addition, the transfusion isattended with the danger of infection by cytomegalovirus or the like.Further, in the case of bone marrow transplantation, it is difficult tofind a donor of bone marrow which is compatible with the bone marrow ofa patient. Moreover, even after the transplantation of bone marrow,several months are required for the number of blood platelets to benormal.

Under such circumstances, muramyldipeptide derivatives (Laid-OpenPublication No. WO 89/01778), human-macrophage-colony-stimulatingfactors (Japanese Laid-Open Patent Publication No. 207244/1989),interleukin-l and derivatives thereof (Japanese Laid-Open PatentPublication No. 138224/1990), human BCDF (Japanese Laid-Open PatentPublication No. 101624/1991) and the like are now being developed astherapeutic agents for the above-described thrombocytopenia. However,none of the above agents can sufficiently fulfill the demands.

Therefore, more efficacious therapeutic agents for thrombocytopenia aredemanded presently.

SUMMARY OF THE INVENTION

As mentioned above, a medicine, or a therapeutic or prophylactic methodeffective for the treatment or prophylaxis of the damage to marrowcells, radiation damage and thrombocytopenia has been demanded.

An object of the present invention is to provide amarrow-cell-proliferation-accelerating agent or method which is highlyeffective for ameliorating various diseases or conditions of diseasescaused by the damage to marrow cells.

Another object of the present invention is to develop a radioprotectiveagent which is extremely effective for the organism, thereby providingan agent or a method for protecting a human against radiation damagewhich can minimize the influence of irradiation with radiation to theorganism, and which shows a high life-span-increasing effect on thosewho are exposed to a lethal dose of radiation.

A further object of the present invention is to develop, inconsideration of the aforementioned present situation, a noveltherapeutic agent for thrombocytopenia, thereby providing a therapeuticagent effective for various types of thrombocytopenia, and alsoproviding a medicine or a method capable of mitigating a decrease ofblood platelets which is a limiting factor upon chemotherapy andradiotherapy for cancer.

Specific α-galactosylceramides were applied to cultured cells andanimals, and their influences were studied. As a result, the followingpoints were found: (1) the compounds have amarrow-cell-proliferation-accelerating effect, (2) they can be aneffective protective means against irradiation with radiation, (3) theyare excellent in a blood-platelet-increasing effect and ablood-platelet-decrease-inhibitory effect, and, in addition, they arequite safe even when administered to the organism. The present inventionhas been accomplished on the basis of the above findings.

The pharmaceutical composition (a marrow cell proliferation accelerator,a radioprotective agent and a therapeutic agent for thrombocytopenia)according to the present invention comprises one or moreα-galactosylceramides represented by the following formula (A) as activeingredients together with a carrier or a diluent: ##STR3## (wherein R₂represents H or OH, X is an integer of 0-26) or --(CH₂)₇ CH=CH(CH₂)₇CH₃, and R₁ is one of the substituents defined by the following (a) to(d): (a) --CH₂ (CH₂)_(y) CH₃, (b) --CH(OH)(CH₂)_(y) CH₃, (c)--CH(OH)(CH₂)_(y) CH(CH₃)₂, and (d) --CH=CH(CH₂)_(y) CH₃ (wherein Y isan integer of 5-17).

In the above formula (A), (1) when R is ##STR4## the compound isrepresented by the following formula (I), and (2) when R is --(CH₂)₇CH=CH(CH₂)₇ CH₃, the compound is represented by the following formula(XXI): ##STR5##

In the method according to the present invention, the method forproliferating marrow cell is characterized by administering an.effective amount of the compound represented by the above formula (A)(formula (I) or (XXI)) to a patient who needs marrow cell proliferation;the method for protecting human against radiation damage ischaracterized by administering an effective amount of the compoundrepresented by the above formula (A) (formula (I) or (XXI)) to a humanwho needs protection against radiation damage; and the method for thetreatment of thrombocytopenia is characterized by administering aneffective amount of the compound represented by the above formula (A)(formula (I) or (XXI)) to a patient who needs inhibition of a reductionin number of blood platelets or an increase in the number of bloodplatelets.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 (a and b) is a diagram showing a reaction route (synthesis routeA) for synthesizing a compound represented by the formula (A), using asa starting material an aldehyde compound.

FIG. 2 is a diagram showing a reaction route (synthesis route B) forsynthesizing a compound represented by the formula (A), using as astarting material an aldehyde compound as mentioned regarding FIG. 1,which route includes fewer steps than the synthesis route A.

FIG. 3 is a diagram showing a reaction route (synthesis route C) forderiving a compound represented by the formula (A) from sphingosine, astarting material, by applying thereto various chemical modifications.

FIG. 4 (a-c) is a diagram showing a reaction route (synthesis route D)for synthesizing, using as a starting material an aldehyde compound, acompound represented by the formula (A) in which the 4-position of thelong-chain base moiety is a hydroxyl group.

FIG. 5 (a and b) is a diagram showing a reaction route which shows apreferable method for synthesizing Compound 9((2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3-tetradecanol).

FIG. 6 is a diagram showing a reaction route which shows a preferablemethod for synthesizing Compound 7((2S,3R)-1-(α-D-galactopyranosyloxy)-2-octanoylamino-3-octadecanol).

FIG. 7 is a diagram showing a reaction route which 30 shows a preferablemethod for synthesizing Compound 5((2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-octadecanol).

FIG. 8 is a diagram showing a reaction route which shows a preferablemethod for synthesizing Compound 1((2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3-octadecanol).

FIG. 9 is a diagram showing a reaction route which shows anotherpreferable method for synthesizing Compound 5.

FIG. 10 (a-c) is a diagram showing a reaction route which shows apreferable method for synthesizing Compound 22((2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxyltetracosanoylamino!-3,4-heptandecanediol).

DETAILED DESCRIPTION OF THE INVENTION COMPOUNDS REPRESENTED BY FORMULA(A)

As mentioned previously, a compound used for the medicine and thetherapeutic (or prophylactic) method according to the present inventionis one having a chemical structure represented by the formula (A) (i.e.the formulas (I) and (XXI)). It is preferable that R₁ in the formula (I)be one of the following (a) to (d):

(a) --CH₂ (CH₂)_(y) CH₃

In the above, when R₂ is H, it is preferable that X be an integer of 0to 24 and Y be an integer of 7 to 15; and when R₂ is OH, it ispreferable that X be an integer of 20 to 24 and Y be an integer of 11 to15. Further, when R₂ is H, it is particularly preferable that X be aninteger of 8 to 22 and Y be an integer of 9 to 13; and when R₂ is OH, itis particularly preferable that X be an integer of 21 to 23 and Y be aninteger of 12 to 14. (b) --CH(OH)(CH₂)YCH₃

In the above, when R₂ is H, it is preferable that X be an integer of 18to 26 and Y be an integer of 5 to 15; and when R₂ is OH, it ispreferable that X be an integer of 18 to 26 and Y be an integer of 5 to17. Further, when R₂ is H, it is particularly preferable that X be aninteger of 21 to 25 and Y be an integer of 6 to 14; and when R₂ is OH,it is particularly preferable that X be an integer of 21 to 25 and Y bean integer of 6 to 16. (c) --CH(OH)(CH₂)YCH(CH₃)₂

In the above, when R₂ is H, it is preferable that X be an integer of 20to 24 and Y be an integer of 9 to 13; and when R₂ is OH, it ispreferable that X be an integer of 20 to 24 and Y be an integer of 9 to13. Further, when R₂ is H, it is particularly preferable that X be aninteger of 21 to 23 and Y be an integer of 10 to 12; and when R₂ is OH,it is particularly preferable that X be an integer of 21 to 23 and Y bean integer of 10 to 12. (d) --CH=CH(CH₂)YCH₃

In the above, it is preferable that R₂ be H, X be an integer of 10 to18, and Y be an integer of 10 to 14. Further, it is particularlypreferable that X be an integer of 11 to 17 and Y be an integer of 11 to13.

On the other hand, it is preferable that R₁ in the formula (XXI) be--CH₂ (CH₂)_(Y) CH₃. In this formula, Y is preferably an integer of 11to 15, and an integer of 12 to 14 is particularly preferred.

Further, among the compounds of the present invention, those compoundswhich are of 2- or 3-coordination as represented by the formula (II)that will be shown later are particularly preferred.

More specific and preferred embodiments of the compounds represented bythe formula (A) (the formulas (I) and (XXI)) can be explained by thefollowing definitions (1) to (35). (1) α-Galactosylceramides of theformula (I), represented by the following formula (II): ##STR6##

In the formula, R₁ is one of the substituents defined by the following(a) to (e), and R₂ represents H or OH (X is defined in the following (a)to (e)). (a) --CH₂ (CH₂)yCH₃

When R₂ is H, X is an integer of 0 to 24 and Y is an integer of 7 to 15;and when R₂ is OH, X is an integer of to 24 and Y is an integer of 11 to15. (b) --CH(OH)(CH₂)YCH₃

When R₂ is H, X is an integer of 18 to 26 and Y is an integer of 5 to15; and when R₂ is OH, X is an integer of 18 to 26 and Y is an integerof 5 to 17. (c) --CH(OH)(CH₂)YCH(CH₃)₂

When R₂ is H, X is an integer of 20 to 24 and Y is an integer of 9 to13; and when R₂ is OH, X is an integer of 20 to 24 and Y is an integerof 9 to 13. (d) --CH=CH--(CH₂)yCH₃

R₂ is H, X is an integer of 10 to 18, and Y is an integer of 0 to 14.(2) α-Galactosylceramides of the formula (I), represented by thefollowing formula (III): ##STR7##

(In the formula, X is an integer of 0 to 24, and Y is an integer of 7 to15.) (3) More preferably, α-galactosylceramides described in the above(2), wherein X is an integer of 8 to 22 and Y is an integer of 9 to 13.(4) Still more preferably, α-galactosylceramides described in the above(2), represented by the following formula (IV): ##STR8##

In the formula, X represents an integer of 0 to 24, and Y represents aninteger of 7 to 15. (5) Most preferably, α-galactosylceramides describedin the above (4), wherein X is an integer of 8 to 22 and Y is an integerof 9 to 13. (6) α-Galactosylceramides of the formula (I), represented bythe following formula (V): ##STR9##

In the formula, X is an integer of 20 to 24, and Y is an integer of 11to 15. (7) More preferably, α-galactosylceramides described in the above(6), wherein X is an integer of 21 to 23 and Y is an integer of 12 to14. (8) Still more preferably, α-galactosylceramides described in theabove (6), represented by the following formula (VI): ##STR10##

In the formula, X is an integer of 20 to 24 and Y is an integer of 11 to15. (9) Most preferably, α-galactosylceramides described in the above(8), wherein X is an integer of 21 to 23 and Y is an integer of 12 to14. (10) α-Galactosylceramides of the formula (I), represented by thefollowing formula (VII): ##STR11##

In the formula, X is an integer of 18 to 26 and Y is an integer of 5 to15. (11) More preferably, α-galactosylceramides described in the above(10), wherein X is an integer of 21 to 25 and Y is an integer of 6 to14. (12) Still more preferably, α-galactosylceramides described in theabove (10), represented by the following formula (VIII): ##STR12##

In the formula, X is an integer of 18 to 26 and Y is an integer of 5 to15. (13) Most preferably, α-galactosylceramides described in the above(12), wherein X is an integer of 21 to 25 and Y is an integer of 6 to14. (14) α-Galactosylceramides of the formula (I), i represented by thefollowing formula (IX): ##STR13##

In the formula, X is an integer of 18 to 26 and Y is an integer of 5 to17. (15) More preferably, α-galactosylceramides described in the above(14), wherein X is an integer of 21 to 25 and Y is an integer of 6 to16. (16) Still more preferably, α-galactosylceramides described in theabove (14), represented by the following formula (X): ##STR14##

In the formula, X is an integer of 18 to 26 and Y is an integer of 5 to17. (17) More preferably, α-galactosylceramides described in the above(14), represented by the following formula (X'): ##STR15##

In the formula, X is an integer of 20 to 24 and Y is an integer of 10 to14. (18) Most preferably, α-galactosylceramides described in the above(16), wherein X is an integer of 21 to 25 and Y is an integer of 6 to16. (19) Most preferably, α-galactosylceramides described in the above(17), wherein X is an integer of 21 to 23 and Y is an integer of 11 to13. (20) α-Galactosylceramides of the formula (I), represented by thefollowing formula (XI): ##STR16##

In the formula, X is an integer of 20 to 24 and Y is an integer of 9 to13. (21) More preferably, α-galactosylceramides described in the above(20), wherein X is an integer of 21 to 23 and Y is an integer of 10 to12. (22) Still more preferably, α-galactosylceramides described in theabove (20), represented by the following formula (XII): ##STR17##

In the formula X is an integer of 20 to 24 and Y is an integer of 9 to13. (23) Most preferably, α-galactosylceramides described in the above(22), wherein X is an integer of 21 to 23 and Y is an integer of 10 to12. (24) α-Galactosylceramides of the formula (I), represented by thefollowing formula (XIII): ##STR18##

In the formula, X is an integer of 20 to 24 and Y is an integer of 9 to13. (25) More preferably, -galactosylceramides described in the above(24), wherein X is an integer of 21 to 23 and Y is an integer of 10 to12. (26) Still more preferably, α-galactosylceramides described in theabove (24), represented by the following formula (XIV'): ##STR19##

In the formula, X is an integer of 20 to 24 and Y is an integer of 9 to13. (27) Most preferably, α-galactosylceramides described in 30 theabove (26), wherein X is an integer of 21 to 23 and Y is an integer of10 to 12. (28) α-Galactosylceramides of the formula (I), represented bythe following formula (XV): ##STR20##

In the formula, X is an integer of 10 to 18 and Y is an integer of 10 to14. (29) More preferably, α-galactosylceramides described in the above(28), wherein X is an integer of 11 to 17 and Y is an integer of 11 to13. (30) Still more preferably, α-galactosylceramides described in theabove (28), represented by the following formula (XVI): ##STR21##

In the formula, X is an integer of 10 to 18 and Y is an integer of 10 to14. (31) Most preferably, α-galactosylceramides described in the above(30), wherein X is an integer of 11 to 17 and Y is an integer of 11 to13. (32) α-Galactosylceramides of the formula (XXI), represented by thefollowing formula (XIX): ##STR22##

In the formula, Y is an integer of 11 to 15. (33) Preferably,α-galactosylceramides described in the above (32), wherein Y is aninteger of 12 to 14. (34) More preferably, α-galactosylceramidesdescribed in the above (32), represented by the following formula (XX):##STR23##

In the formula, Y is an integer of 11 to 15. (35) Most preferably,α-galactosylceramides described in the above (34), wherein Y is aninteger of 12 to 14.

Preferred, specific examples of the compounds represented by the formula(A) (the formulas (I) and (XXI)) are as follows. In each formula, X andY are the same as before.

(1) Compounds represented by the following formula (III) or (VI):##STR24##

Compound 1:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3-octadecanol,

Compound 2:(2S,3R)-2-docosanoylamino-1-(α-D-galactopyranosyloxy)-3-octadecanol,

Compound 3:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-icosanoylamino-3-octadecanol,

Compound 4:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-octadecanoylamino-3-octadecanol,

Compound 5:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-octadecanol,

Compound 6:(2S,3R)-2-decanoylamino-1-(α-D-galactopyranosyloxy)-3-octadecanol,

Compound 7:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-octanoylamino-3-octadecanol,

Compound 8:(2S,3R)-2-acetamino-1-(α-D-galactopyranosyloxy)-3-octadecanol,

Compound 9:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3-tetradecanol,

Compound 10:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-hexadecanol,

Compound 11:(2R,3S)-1-(α-D-galactopyranosyloxy)-2-tetradecanoyiamino-3-hexadecanol,

Compound 12:(2S,3S)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-hexadecanol,

Compound 13:(2R,3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-hexadecanol,and

Compound 14: (2S,3R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3-octadecanol.

Of these compounds, Compounds 1-10 and 14 are preferred because they areof 2- or 3-coordination. (2) Compounds represented by the followingformula (XVI): ##STR25##

Compound 15:(2S,3R,4E)-1-(α-D-galactopyranosyloxy)-2-octadecanoylamino-4-octadecen-3-ol,and

Compound 32:(2S,3R,4E)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-4-octadecen-3-ol.

(3) Compounds represented by the following formula (VIII): ##STR26##

Compound 16:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3,4-octadecanediol,

Compound 17:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3,4-heptadecanediol,

Compound 18:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3,4-pentadecanediol,

Compound 19:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoylamino-3,4-undecanediol,

Compound 20:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-heptadecanediol,

Compound 33:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoylamino-3,4-octadecanediol,and

Compound 34:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-octacosanoylamino-3,4-heptadecanediol.

(4) Compounds represented by the following formula (X) or (X'):##STR27##

Compound 21: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3,4-octadecanediol,

Compound 22: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3,4-heptadecanediol,

Compound 23: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3,4-pentadecanediol,

Compound 24: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3,4-undecanediol,

Compound 25: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxytetracosanoylamino!-3,4-octadecanediol,

Compound 26: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxyhexacosanoylamino!-3,4-nonadecanediol,

Compound 27: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxyhexacosanoylamino!-3,4-icosanediol, and

Compound 28: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(S)-2-hydroxytetracosanoylamino!-3,4-heptadecanediol. (4) Compoundsrepresented by the following formula (XII) or (XIV'): ##STR28##

Compound 30: (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(S)-2-hydroxytetracosanoylamino!-16-methyl-3,4-heptadecanediol, and

Compound 31:(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-16-methyl-2-tetracosanoylamino-3,4-heptadecanediol.

(5) Compound represented by the following formula (XIX): ##STR29##

Compound 29:(2S,3R)-1-(α-D-galactopyranosyloxy)-2-oleoylamino-3-octadecanol.

Method for Preparing Compounds-Represented by Formula (A) (Outline)

These compounds can be chemically synthesized by the method described inthe Application No. PCT/JP92/00561 which was filed by the inventors ofthe present invention.

An α-galactosylceramide represented by the above formula (A) (theformulas (I) and (XXI)) can be derived from sphingosine by applyingthereto various chemical modifications. However, it is also possible tosynthesize the α-galactosylceramide by a chemical synthesis method inwhich various general chemical reactions necessary for the synthesis ofsphingoglycolipid are used in combination. There is no single route ofsynthesis and a desired compound can be derived from a differentstarting material via a different route. The compound can also besynthesized by utilizing a general chemical synthesis method regardingsphingoglycolipid, for example, by the method described in "Agriculturaland Biological Chemistry", Vol. 54, No. 3, p. 663 (1990). It can also besynthesized, for example, by the method described in "Liebigs Annalender Chemie", p. 663 (1988), in which method various saccharides are usedas starting materials. In these synthesis methods, a protective group isremoved after sugar is combined with a ceramide. However, it is alsopossible to adopt the method as described in "Liebigs Annalen derChemie", p. 669 (1988), in which method sugar is firstly combined with along-chain base and then amidation is conducted by introducing an aminogroup to obtain cerebroside. (Synthesis Route A)

As an example of the above-described synthesis can be mentioned thefollowing process by which the compounds represented by the aboveformula (III), (V) or (XIX) can be synthesized (see FIG. 1, a and b).

In FIG. 1, the following abbreviations are used:

Bn: benzyl,

R4: hydroxyl group or formyloxy group,

Ms: methanesulfonyl,

R5: hydrogen atom or acyloxy group,

Tr: triphenylmethyl, and

Bz: benzoyl.

The aldehyde used as a starting material has 1 or 2 points of asymmetry.Amino acid or saccharide can be utilized as an asymmetry-causing source.In this example, a benzyl group is used as a hydroxy-protective group.However, any group which is fit for the purpose, such as anisopropylidene group, can also be used.

In particular, regarding the amidation in the route shown in thediagram, many reaction methods are known.

Instead of using carboxylic acid, an acid chloride or an acid anhydridecan be used.

The reaction using carboxylic acid is a condensation reaction which iscarried out in the presence of a proper condensation agent. Examples ofthe condensation agent herein used include dicyclohexylcarbodiimide(DCC), 2-et-hoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), chlorocarbonatesand onium salts. In order to accelerate the reaction, an organic basesuch as triethylamine, pyridine, N-methylmorpholine, dimethylaniline,4-dimethylaminopyridine, N-methylpiperidine or N-methylpyrrolidine isadded. Any inert solvent which does not participate in the reaction canbe used.

In general, a reaction using an acid chloride conveniently proceeds inthe presence of a solvent. The reaction is usually carried out by usinga proper solvent. However, when the reaction speed. is low, it issuitable to carry out the reaction in the absence of a solvent. Thereaction can thus be accelerated. Any solvent can be used as long as itis inert and does not participate in the reaction. In the case where thereaction speed is low., the addition of an organic base such astriethylamine, pyridine, N-methylmorpholine, dimethylaniline or4-dimethylaminopyridine is sometimes useful for accelerating thereaction.

A reaction using an acid anhydride is preferably carried out in thepresence of a proper base. A base herein used is triethylamine, pyridineor the like, and, in general, these bases also serve as solvents.

Further, many reaction methods regarding glycosylation are also known,and they are summarized in the following references: (1) "OrganicSynthetic Chemistry", Vol. 38, No. 5, p. 473 (1980), (2) "OrganicSynthetic Chemistry", Vol. 41, No. 8, p. 701 (1983) and (3) "Pure andApplied Chemistry", Vol. 61, No. 7, p. 1257 (1991).

Any of the above reactions can be employed. However, a method in whichα-galactoside is preferentially obtained (for example, the methoddescribed on pages 431-432 of "Chemistry Letters" (1981)) is preferred.When an α-compound cannot be solely obtained, separation between α- andβ-compounds is conducted. However, when it is difficult to conduct thisseparation, it is suitable to change a hydroxyl group to an acylderivative (for example, acetyl). The separation between the α- andβ-compounds is thus made possible. (Synthesis Route B)

The following reaction route can be presented as a shorter processstarting with the same starting material as in the synthesis route A.The compounds represented by the above formula (III), (V) or (XIX) canalso be synthesized by this method (see FIG. 2). The abbreviations usedin FIG. 2 are the same as before. This route is characterized in thatreduction of an azido group, elimination of a benzyl group and reductionof a double bond are simultaneously conducted upon reduction of an azidecompound. The number of steps in the route is thus reduced. By thereduction, 2-amino-1,3-alkanediol can be obtained as an intermediate.Four respective isomers of this compound can be singly obtained byproperly selecting an asymmetry-causing source for the aldehyde used asa starting material. The isomers obtained are separately subjected toamidation. In this process, various methods of amidation as described inthe route A are employable. After this, glycosylation and deprotectionare conducted in the same manner as in the route A to obtain a desiredcompound. (Synthesis Route C)

One example of synthesis in which compounds are derived from sphingosineby applying thereto various chemical modifications is thebelow-described process. Of the compounds represented by the aboveformula (IV), (VI), (XVI) or (XX), those compound whose long-chain basemoiety contains 18 carbon atoms can also be synthesized by this process(see FIG. 3). The abbreviations used in FIG. 3 are the same as before.Sphingosine can be extracted from natural product. However, it iscommercially available from Sigma Chemical Company, Funakoshi Co., Ltd.or the like. It can also be synthesized by one of various synthesismethods described in "Pharmacia", Vol. 27, p. 1164 (1991) and "Journalof the Chemical Society Perkin Transactions 1", p. 2279 (1991). Isomersof sphingosine which are different from natural products in theconfiguration can also be synthesized by the method described in"Helvetica Chimica cta", Vol. 40, p. 1145 (1957) or "Journal of theChemical Society Chemical Communications", p. 820 (1991). In the latterreference cited, many synthesis examples are described. According tothis route, it is possible to leave a double bond even afterglycosylation. Namely, when catalytic reduction is carried out for finaldeprotection, a compound having no double bond can be obtained; and whena protected compound is treated with metal sodium in liquid ammonia forfinal deprotection, a compound with a double bond remaining can beobtained. A desired compound can thus be obtained. (Synthesis Route D)

Of those compounds which have a hydroxyl group at the 4-position of along-chain base in the formula (A), compounds represented by the formula(VII), (IX), (XI), (XIII) or (XVII) can also be synthesized via thefollowing process (see FIG. 4(a-c)). The abbreviations used in FIG. 4are the same as those used in the above process.

The aldehyde, a starting material, can be freely made into its isomersby properly selecting an asymmetry-causing source, and the respectiveisomers can be obtained singly. The isomers thus obtained are separatelysubjected to the subsequent Wittig reaction. It is easy to change theterminal end of the Wittig salt to an iso type, an anti-iso type or astraight-chain type. In general, the Wittig reaction using such anunstable ylide gives, as a main product, a compound having a cis-typedouble bond. However, a compound having a trans-type double bond is alsoproduced. A mixture of such compounds is acceptable because the doublebonds contained in the mixture are changed into single bonds in the stepof catalytic reduction. Mesylation and azido inversion are conducted,followed by reduction to give an amino group which is subjected toamidation in the subsequent step to give a ceramide. Such a protectedceramide, an intermediate, can also be repared by using as a startingmaterial Cereblin E (a roduct of Alfred Bader Chemicals or K & KLaboratories, Inc.), and protecting it with a protective group which isfit for the purpose. Further, in order to distinguish from the othergroups a hydroxyl group with which sugar is combined, it is protectedand deprotected, and then glycosylated and deprotected to give a desiredcompound (FIG. 4).

Pharmaceutical Composition and Therapeutic (or Prophylactic) Method

As mentioned previously, the pharmaceutical composition or medicine (amarrow cell proliferation accelerator, a radioprotective agent, atherapeutic agent for thrombocytopenia) according to the presentinvention comprises as an active ingredient at least one compoundrepresented by the formula (A) (i.e. the formulas (I) and (XXI))together with a carrier or a diluent; and the therapeutic orprophylactic method (a method for proliferating marrow cells, a methodfor protecting human against radiation damage, a method for thetreatment of thrombocytopenia) according to the present inventioncomprises administering an effective amount of a compound represented bythe formula (A) (the formula (I) or (XXI)) to human.

In the present invention, the compounds represented by the formula (A)have a marrow-cell-proliferation-accelerating effect, so that they areconsidered to be effective for the amelioration or treatment of severeinfectious diseases, blood dyscrasia (e.g. leukemia andosteomyelodysplasia), liver cirrhosis, splenomegaly, systematic lupuserythematosus, and a drastic decrease in the number of marrow cellscaused by administration of an anticancer agent, or upon radiotherapy,and to be useful for accelerating marrow cell proliferation at the timeof bone marrow transplantation.

Further, in the present invention, the compounds represented by theformula (A) have a radioprotective effect. Therefore, they showextremely excellent prophylactic and therapeutic effects when they areadministered before or after irradiation with radiation, and, inparticular, show an excellent life-span-increasing effect againstirradiation of a lethal dose of radiation.

Furthermore, in the present invention, the compounds represented by theformula (A) have excellent blood-platelet-increasing andblood-platelet-decrease-inhibitory effects. Therefore, when they areadministered to a patient of thrombocytopenia, or to the organism whoseblood platelets are decreased in the number due to chemotherapy orradiotherapy for cancer, they show an excellentblood-platelet-increasing effect or blood-platelet-decrease-inhibitoryeffect.

The compounds represented by the formula (A), used for the medicine orthe method according to the present invention can be administered by anyadministration route -which is fit for the purpose. Specifically, thecompounds can be administered to animals by any one of such methods asintraperitoneal administration, subcutaneous administration, vascularadministration such as intravenous or intra-arterial administration, andtopical administration by injection; and they can be administered to ahuman by any one of such methods as intravenous administration,intra-arterial administration, topical administration by injection,administration to peritoneal or pleural cavity, oral administration,subcutaneous administration, intramuscular administration, sublingualadministration, percutaneous administration and rectal administration.

Further, the compounds represented by the formula (A), used for themedicine and the method according to the present invention can beadministered in a form properly determined depending on the method andthe purpose of administration, specifically in a form of injection,suspension, emulsion, tablet, granule, powder, capsule, troche,ointment, dry syrup or cream. Upon producing these preparations, apharmaceutically acceptable additive such as a carrier or diluent,specifically, a solvent, a solubilizing agent, an isotonicating agent, apreservative, an antioxidant, an excipient, a binding agent, alubricant, a stabilizer or the like may be added.

Examples of the solvent include distilled water for injections andphysiological saline. Examples of the solubilizing agent includeethanol, Polysorbates and Macrotigols. Examples of the excipient includelactose, starch, crystalline cellulose, mannitol, maltose, calciumhydrogenphosphate, light silicic acid anhydride and calcium carbonate.Examples of the binding agent include starch, polyvinylpyrrolidone,hydroxypropylcellulose (HPC), ethylcellulose, carboxymethylcellulose andgum arabic. Examples of the disintegrator include starch andcarboxymethylcellulose calcium (CMC--Ca). Examples of the lubricantinclude magnesium stearate, talc and hardened oil. Examples of thestabilizing agent include lactose, mannitol, maltose, Polysorbates,Macrogols and polyoxyethylene hardened castor oil. Further, glycerin,dimethylacetamide, 70% sodium lactate, a surface active agent, and abasic material (for example, ethylene diamine, ethanol amine, sodiumcarbonate, arginine, Meglumine, trisaminomethane) may also be added, ifnecessary. By using these ingredients, the above-described preparationscan be obtained.

The dose of the compound represented by the formula (A) (i.e. theformulas (I) and (XXI)) used for the medicine and the method accordingto the present invention is determined, in consideration of the resultsobtained by tests using animals and the particular condition, so as notto exceed a predetermined amount when the compound is administeredcontinuously or intermittently. It is needless to say that the specificdose varies depending on administration route, the state of a patient ora test animal, such as age, body weight, sex and sensitivity, diet, timefor administration, drugs to be used in combination, and the conditionof a patient or a disease. Further, the optimum dose and the frequencyof administration under a certain condition should be determined by aspecialist on the basis of the above-described guidelines and theresults of an optimum dose determining test. The dose at which thecompound represented by the formula (A) reveals its activity is, ingeneral, approximately 0.01 to 100 mg/day per human adult. This rangewas determined on the basis of the dose for intravenous administrationto a croo monkey, and that for oral administration to a mouse.

Referential Examples

The method for preparing specific compounds represented by the formula(A), used for the medicine and the method according to the presentinvention is described in the specification of the PCT Application(PCT/JP92/00561) mentioned previously.

The methods for synthesizing these compounds and the physicochemicalproperties of the compounds are as follows (see the synthesis routesshown in FIGS. 1 to 10):

(1) Synthetic route A

While this reaction route scheme is shown specifically with reference tothe aforementioned compound 9, the compounds 1-8 and 10-14 according tothe present invention can also be synthesized by applying this method(see FIGS. 5a and 5b).

In the above scheme, the following abbreviations are used.

DMAP: 4-dimethylaminopyridine, TsOH: p-toluenesulfonic acid, MS-4A:Molecular Sieves-4A (dehydrating agent).

The other abbreviations have the same meanings as in the previous routeschemes.

Furthermore, the compound 29 leaving a double bond unreacted therein canbe synthesized by the use of a fatty acid having a double bond as astarting material and by the deprotection at the final step with liquidammonia and metallic sodium. Synthesis of the compound 9 (FIGS. 5a and5b)!

The compound Al can be synthesized in accordance with the methoddescribed in Synthesis, 961-963, 1984. (i) Synthesis of the compound A2

To a solution of the compound Al (2.89 g) in 2-methyl-2-propanol (25 ml)was added a 5% aqueous sulfuric acid solution (25 ml), and the mixturewas stirred at 45° C. for 15 hours. After being neutralized with powderysodium hydrogen carbonate under ice-cooling, the reaction mixture wasconcentrated. The residue, to which water (30 ml) was added, wasextracted with ethyl acetate (three times), and the organic layer wasconcentrated. Purification on a silica gel column (Wako Gel C-200, 100g) using hexane-acetone (2:1) as an eluent afforded a diol in an amountof 2.28 g (yield: 88.5%). MS: FDMS 330.

The mixture of the diol (2.25 g) with ethanol (50 ml), water (12 ml) andsodium metaperiodate (2.33 g) was stirred at room temperature for 10hours. Precipitates were removed by filtration, and the filtrate wasconcentrated. The residue was diluted with chloroform and washed withbrine. The organic layer was concentrated to give an aldehyde (compoundA2) in an amount of 1.31 g. The aldehyde was directly used for the nextreaction without purification. (ii) Synthesis of the compound A3

To decanetriphenylphosphonium bromide (8.0 g) was added tetrahydrofuran(20 ml) under an argon atmosphere. After adding a 2.8 N solution ofn-butyllithium in hexane (6.2 ml) to the mixture at -10° C., stirringwas continued for 30 minutes. After the addition of the aldehyde(compound A2, 1.31 g) dissolved in tetrahydrofuran (5 ml), the mixturewas allowed to warm to room temperature and stirred for 15 hours andconcentrated. The reaction mixture was diluted with brine, and extractedtwice with ethyl acetate. The organic layer was washed with brine andconcentrated. Purification of the residue on a silica gel column (WakoGel C-200, 100 g) by eluting with hexane-ethyl acetate (5:1) gave thealcohol (compound A3) in an amount of 1.47 g (yield, 51.0%). Data of thecompound A3 MS: FDMS 426. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (Ppm) 7.25-7.35 (10H, m), 5.69-5.79 1H, (5.75, dt, J=7.3, 11.0 Hz),(5.72, dt, J=6.7, 15.2 Hz)!, 5.31-5.38 1H, (5.36, bt, J=8.5 Hz), (5.33,bt, J=9.8 Hz)!, 4.34-4.62 2H, (4.61 & 4.35, ABq, J=11.6 Hz), (4.56 &4.50, ABq, J=12.2 Hz), (4.55 & 4.52, ABq, J=11.6 Hz)!, 4.28 (0.7H, dd,J=6.7, 9.7 Hz), 3.85 (0.3H, bt, J=7.9 Hz), 3.74-3.78 (1H, m), 3.56-3.601H (3.59, dd, J=3.1, 9.8 Hz), (3.58, overlapped)!, 3.47 (IH, dd, J=5.5,9.8 Hz), 1.96-2.11 (1H, m), 1.25-1.57 (14H, m), 0.88 (3H, t, J=6.7 Hz).

(iii) Synthesis of the compound A4

The alcohol (compound A3, 0.83 g) was dissolved in tetrahydrofuran (10ml). 10% Palladium on charcoal (1.0 g) was added, and the reactionvessel was purged with hydrogen. After the mixture was stirred at roomtemperature for 12 hours, it was filtered through celite and thefiltrate was concentrated. Purification on a silica gel column (Wako GelC-200, 30 g) eluting with hexane-ethyl acetate (5:1) afforded areduction product (compound A4) in an amount of 0.81 g (yield, 97.1%).Data of the compound A4 MS: FDMS 428. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.25-7.46 (JOH, m), 4.50 & 4.62 (2H, ABq, J=11.0 Hz), 4.54 (2H,s), 3.79-3.83 (1H, m), 3.48-3.56 (3H, m), 2.42 (1H, d, J=6.1 Hz),1.26-2.04 (20H, m), 0.88 (3H, t, J=7.3 Hz).

(iv) Synthesis of the compound A5

After adding methanesulfonyl chloride (0.29 ml) to the reduction product(compound A4, 0.80 g) in pyridine (15 ml), the mixture was stirred atroom temperature for 16 hours. The reaction mixture was concentrated anddistilled azeotropically with toluene. The residue dissolved in diethylether was washed with brine and concentrated. Purification on a silicagel column (Wako Gel C-200, 30 g) eluting with hexane-acetone (6:1)afforded a mesylated product (compound A5) in an amount of 0.87 g(yield, 91.9%). Data of the compound A5 MS: FDMS 504. NMR: ¹ H (500 MHz,CDCl₃ ; 27° C.)

δ (ppm) 7.27-7.38 (1OH, m), 4.81-4.84 (1H, m), 4.59 (2H, s), 4.55 & 4.50(2H, ABq, J=11.6 Hz), 3.75 (1H, dd, J=3.1, 11.0 Hz), 3.71 (1H, dd,J=6.7, 11.0 Hz), 3.67 (1H, dt, J=4.3, 8.5 Hz), 2.99 (3H, s), 1.24-1.64(20H, m), 0.88 (3H, t, J=7.3 Hz).

(v) Synthesis of compound A6

To the mesylated product (compound A5, 0.86 g) were addeddimethylformamide (10 ml) and sodium azide (885 mg), and the mixture wasstirred at 120° C for 15 hours. The reaction mixture was diluted withbrine, extracted with ethyl acetate (three times), and thenconcentrated. Purification on a silica gel column (Wako Gel C-200, 30 g)eluting with hexane-ethyl acetate (40:1) afforded an azide (compound A6)in an amount of 0.73 g (yield, 94.3%). Data of the compound A6 MS: FDMS453. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.27-7.44 (10H, m), 4.54 & 4.58 (2H, ABq, J=12.2 Hz), 4.52 &4.57 (2H, ABq, J=ll.0 Hz), 3.68-3.70 (2H, m), 3.63 (1H, dd, J=8.5, 11.0Hz), 3.53 (1H, dt, J=4.3, 8.6 Hz), 1.25-1.64 (20H, m), 0.88 (3H, t,J=6.7 Hz).

(vi) Synthesis of the compound A7

To the azide (compound A6, 0.72 g) were added tetrahydrofuran (7 ml) and10% palladium on charcoal (70 mg), and the mixture was stirred at roomtemperature after the reaction vessel was purged with hydrogen. Thereaction mixture was filtered through celite, and the filtrate wasconcentrated. Purification on a silica gel column (Wako Gel C-200, 15 g)eluting with hexane-acetone (6:1) afforded an amine (compound A7) in anamount of 0.62 g (yield, 91.5%). Data of the compound A7 MS: FDMS 427.NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.27-7.36 (1OH, m), 4.51 & 4.54 (2H, ABq, J=11.6 Hz), 4.52 (2H,s), 3.58 (1H, dd, J=3.7, 9.2 Hz), 3.41-3.45 (2H, m), 3.20 (1H, dt,J=4.3, 7.3 Hz), 1.26-1.63 (20H, m), 0.88 (3H, t, J=6.7 Hz).

(vii) Synthesis of the compound A8

To the amine (compound A7, 0.61 g) were added methylene chloride (20ml), 2-chloro-1-methylpyridinium iodide (483 mg) and n-tributylamine(0.45 ml). Tetracosanic acid (597 mg) was further added, and the mixturewas heated under reflux for 2 hours. The reaction mixture was cooled toroom temperature, washed sequentially with 5% aqueous sodium thiosulfatesolution, 5% aqueous sodium hydrogen carbonate solution and brine, andthen concentrated. Purification on silica gel column (Wako Gel C-200, 20g) eluting with hexane-acetone (20:1) afforded an amide (compound A8) inan amount of 0.56 g (yield, 51.2%). Data of the compound A8 MS: FDMS777. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.28-7.35 (1OH, m), 5.66. (1H, d, J=9.2 Hz), 4.45 & 4.58 (2H,ABq, J=11.6 Hz), 4.48 (2H, s), 4.25-4.30 (1H, m), 3.73 (1H, dd, J=4.9,9.8 Hz), 3.57 (1H, dt, J=5.5, 6.7 Hz), 3.52 (1H, dd, J=4.3, 9.8 Hz),2.08 (2H, dt, J=3.1, 10.4 Hz), 1.26-1.58 (64H, m), 0.88 (6H, t, J=6.7Hz).

(viii) Synthesis of the compound A9

To the amide (compound A8, 0.55 g) were added tetrahydrofuran (15 ml)and palladium black (55 mg). The reaction vessel was purged withhydrogen, and the mixture was stirred at room temperature for 16 hours.The reaction mixture was filtered through celite, and the filtrate wasconcentrated. Purification on a silica gel column (Wako Gel C-200, 20 g)eluting with chloroform-methanol (20:1) afforded a diol (compound A9) inan amount of 302 mg (yield, 71.6%). Data of the compound A9 MS: FDMS597. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.34 (1H, d, J=7.9 Hz), 4.62-4.67 (1H, m), 4.46 (1H, dd, J=4.9,11.0 Hz), 4.30 (1H, dd, J=5.8, 11.6 Hz), 4.25-4.32 (1H, m), 2.48 (2H,dt, J=2.4, 7.3 Hz), 1.23-1.97 (62H, m), 0.88 (6H, t, J=6.7 Hz).

(ix) Synthesis of the compound A10

To the diol (compound A9, 70 mg) were added pyridine (5 ml),triphenylmethyl chloride (261 mg) and 4-dimethylaminopyridine (5 mg),and the mixture was stirred at 60° C. for 2 hours. The reaction mixturewas diluted with chloroform, washed with brine and concentrated.Purification on a silica gel column (Wako Gel C-200, 10 g) eluting withchloroform-acetone (100:1) afforded a tritylated derivative (compoundA10) in an amount of 90.2 mg (yield, 91.6%). Data of the compound A10MS: FDMS 837. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.25-7.47 (15H, m), 6.28 (1H, d, J=7.9 Hz), 3.93-3.96 (1H, m),3.58-3.61 (1H, m), 3.52 (1H, dd, J=3.1, 9.8 Hz), 3.26 (1H, dd, J=3.7,9.8 Hz), 2.95 (1H, d, J=9.2 Hz), 2.24 (2H, t, J=7.3 Hz), 1.25-1.70 (62H,m), 0.88 (6H, t, J=7.3 Hz).

(x) Synthesis of the compound All

To the trityl derivative (compound A10, 87 mg) in pyridine (3.0 ml) wereadded benzoyl chloride (24 μl) and 4-dimethylaminopyridine (3 mg), andthe mixture was stirred for 4 hours. After the mixture to whichice-water had been added was stirred for 30 minutes, it was diluted withchloroform, washed with water and concentrated. Purification on a silicagel column (Wako Gel C-200, 10 g) eluting with hexane-ethyl acetate(10:1) afforded a benzoyl derivative (compound All) in an amount of 83.4mg (yield, 85.3%). Data of the compound All MS: FDMS 941. NMR: ¹ H (500MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.16-7.93 (20H, m), 5.74 (1H, d, J=9.2 Hz), 5.34-5.37 (1H, m),4.39-4.48 (1H, m), 3.40 (1H, dd, J=3.7, 9.8 Hz), 3.19 (1H, dd, J=3.7,9.8 Hz), 2.09 (2H, dt, J=2.5, 9.8 Hz), 1.25-1.74 (64H, m), 0.88 & 0.87(each 3H, t, J=7.3 Hz).

(xi) Synthesis of the compound A12

To the benzoyl derivative (compound All, 80 mg) were added methylenechloride (1.0 ml) and methanol (0.5 ml). p-Toluenesulfonic acidmonohydrate (20 mg) was added, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with ethylacetate, washed with a 5% aqueous sodium hydrogen carbonate and brine,and then concentrated. Purification on a silica gel column (Wako GelC-200, 5 g) eluting with hexane-ethyl acetate (2:1) afforded an alcohol(compound A12) in an amount of 58 mg (yield, 93.6%). Data of thecompound A12 MS: FDMS 701. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.46-8.06 (5H, m), 6.25 (1H, d, J=8.5 Hz), 5.06-5.09 (1H, m),4.15-4.19 (1H, m), 3.58-3.68 (2H, m), 2.23 (2H, t, J=6.7 Hz), 1.22-1.77(62H, m), 0.88 & 0.87 (each 3H, t, J=7.3 Hz).

(xii) Synthesis of the compound A14

A solution of the alcohol (compound A12, 58 mg) in tetrahydrofuran (3.0ml) was stirred with stannous chloride (37 mg), silver perchlorate (41mg) and Molecular Sieves 4A powder (300 mg). After stirring for 30minutes, the mixture was cooled to -10° C., and a solution of benzylgalactosyl fluoride (compound A13, 68 mg) in tetrahydrofuran (1.5 ml)was added. The mixture was allowed to warm gradually to roomtemperature, stirred for 2 hours and filtered through celite. Thefiltrate was concentrated. Purification on a silica gel column (Wako GelC-200, 5 g) eluting with hexane-ethyl acetate (5:1) afforded anα-galactoside (compound A14) in an amount of 62.6 mg (yield, 61.8%).Data of the compound A14 MS: FDMS 1224. NMR: ¹ H (500 MHz, CDCl₃ ; 27°C.)

δ (ppm) 8.02 (2H, d, J=7.3 Hz), 7.56 (1H, t, J=7.9 Hz), 7.43 (2H, t,J=7.9 Hz), 7.23-7.39 (20H, m), 6.58 (1H, d, J=9.2 Hz), 5.30 (1H, dt,J=3.7, 7.9 Hz), 4.90 & 4.55 (2H, ABq, J=11.6 Hz), 4.77 & 4.69 (2H, ABq,J=11.6 Hz), 4.75 (1H, d, J=3.7 Hz), 4.73 & 4.65 (2H, ABq, J=12.2 Hz),4.47 & 4.38 (2H, ABq, J=12.2 Hz), 4.30-4.34 (1H, m), 4.10-4.12 (1H, m),4.01 (1H, dd, J=3.7, 9.8 Hz), 3.97 (1H, dd, J=3.7, 12.2 Hz), 3.84-3.93(2H, m), 3.57 (1H, dd, J=3.1, 12.2 Hz), 3.52 (1H, dd, J=7.3, 9.2 Hz),3.29 (1H, dd, J=4.3, 9.8 Hz), 1.98-2.09 (2H, m), 1.18-1.68 (62H, m),0.88 (3H, t, J=6.7 Hz), 0.86 (3H, t, J=7.3 Hz).

(xiii) Synthesis of the compound A15

To the α-galactoside (compound A14, 56 mg) were added tetrahydrofuran(4.0 ml) and palladium black (15 mg), and the mixture was stirred atroom temperature for 16 hours after the reaction vessel was purged withhydrogen. The reaction mixture was filtered through celite, concentratedand purified on a silica gel column (Wako Gel C-200, 2 g) eluting withchloroform-methanol (20:1) to give a tetraol (compound A15) in an amountof 37.4 mg (yield, 94.7%). Data of the compound A15 MS: FDMS 863. NMR: ¹H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 8.04 (2H, d, J=7.9 Hz), 7.62 (1H, t, J=7.9 Hz), 7.48 (2H, t,J=7.3 Hz), 6.16 (1H, d, J=9.2 Hz), 5.21-5.24 (1H, m), 4.81 (1H, d, J=2.4Hz), 4.45-4.46 (1H, m), 4.08 (1H, bs), 3.91-3.94 (1H, m), 3.87 (1H, dd,J=2.4, 10.4 Hz), 3.75-3.85 (4H, m), 3.57 (1H, dd, J=5.5, 11.6 Hz), 2.22(2H, dt, J=1.8, 7.3 Hz), 1.22-1.79 (62H, m), 0.88 (3H, t, J=7.3 Hz),0.87 (3H, t, J=6.7 Hz).

(xiv) Synthesis of the compound 9

To the tetraol (compound A15, 36.0 mg) were added methanol (3 ml) and alN methanolic sodium methoxide solution (0.3 ml), and the mixture wasstirred for 2 hours. The mixture was neutralized with resins (Dowex 50W,X8; manufactured by The Dow Chemical Company), and then filtered. Thesolids removed was washed sufficiently with chloroform-methanol (1:1),and the extract was combined with the filtrate, and then concentrated.Purification on a silica gel column (Wako Gel C-200, 2 g) eluting withchloroform-methanol (10:1) afforded the compound 9 in an amount of 29.7mg (yield, 94.0%). Data of the compound 9 α!²³ _(D) =+49.0° (pyridine,c=1.31) MS: FDMS 759. IR: (cm⁻¹, KBr) 3200, 2870, 2800, 1630, 1530,1450, 1080. mp: 151°-155° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.49 (1H, d, J=8.6 Hz), 6.11-6.52 (5H, m), 5.45 (1H, d, J=3.7Hz), 4.73 (1H, m), 4.65 (1H, dd, J=3.8, 10.4 Hz), 4.53-4.57 (2H, m),4.43-4.49 (4H, m), 4.36 (1H, dd, J=5.5, 10.4 Hz), 4.27 (1H, m), 2.47(2H, t, J=6.7 Hz), 1.83-1.91 (4H, m), 1.23-1.56 (58H, m), 0.88 (6H, t,J-7.3 Hz).

¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.1 (d), 73.1 (d), 71.9 (d), 71.7 (d), 71.0 (d),70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.7 (t), 29.6 (t),26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).

(2) Synthetic route B

While this scheme specifically illustrates the synthetic routes of theaforementioned compounds 7 and 5, the compounds according to the presentinvention (1-4, 6, 8-14) can also be synthesized by applying thismethod. Synthesis of the compound 7 (FIG. 6)!

Abbreviations in the aforementioned scheme are the same as those in thepreviously described scheme. (i) Synthesis of the compound B1

To tetradecanetriphenylphosphonium bromide (213.7 g) was addedtetrahydrofuran (630 ml), and the reaction vessel was purged with argon.A 2.3N solution of n-butyl lithium in hexane (173 ml) was added at -30°C., and the mixture was stirred for 3.5 hours. A (2R,3R) -aldehyde(compound A2, 31.73 g) dissolved in tetrahydrofuran (630 ml) was addeddropwise, and the mixture was stirred for 2 hours and then concentrated.The residue was diluted with ethyl acetate, washed with water and brine,and then concentrated. Purification on a silica gel column (Wako GelC-200, 850 g) eluting with hexane-ethyl acetate (9:1) afforded analcohol (compound B1) in an amount of 36.31 g (yield, 79.0%). Data ofthe compound B1 MS: FDMS 481. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.26-7.46 (1OH, m), 5.69-5.78 (1H, m), 5.31-5.38 (1H, m),4.34-4.63 (5H, m), 4.28 (0.7H, dd, J=6.7, 9.2 Hz), 3.85 (0.3H, t, J=7.3Hz), 3.75-3.78 (1H, m), 3.56-3.60 (1H, m), 3.47 (1H, dd, J=5.5, 10.4Hz), 1.98-2.11 (2H, m), 1.26-1.34 (22H, m), 0.88 (3H, t, J=6.7 Hz).

(ii) Synthesis of the compound B2

To a solution of the alcohol (compound B1, 5.03 g) in pyridine (50 ml)was added methanesulfonyl chloride (1.62 ml), and the mixture wasstirred at room temperature for 16 hours. The mixture was concentratedand a residual acid chloride was distilled azeotropically together withtoluene. The residue was diluted with diethyl ether, washed with brine,and then concentrated. Purification on a silica gel column (Wako GelC-200, 200 g) eluting with hexane-acetone (10:1) afforded a mesylderivative (compound B2) in an amount of 5.20 g (yield, 88.9%).

Data of the compound B2 MS: FDMS 558. MR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (pPm) 7.23-7.35 (1OH, m), 5.77-5.83 (1H, m), 5.26-5.35 (1H, m),4.71-4.77 (1H, m), 4.33-4.62 (5H, m), 4.06 (0.3H, t, J=8.1 Hz), 3.74(0.7H, dd, J=3.1, 11.0 Hz), 3.65-3.70 (1H, m), 2.964 (0.9H, s), 2.956(2.1H, s), 1.99-2.17 (2H, m), 1.26-1.37 (22H, m), 0.88 (3H, t, J=6.8Hz).

(iii) Synthesis of the compound B3

To the mesyl derivative (compound B2, 1.52 g) were addeddimethylformamide (20 ml) and sodium azide (1.42 g). After stirring at120° C. for 12 hours, the mixture was diluted with brine, extracted withethyl acetate (three times), and then concentrated. Purification on asilica gel column (Wako Gel C-200, 50 g) eluting with hexane-ethylacetate (40:1) afforded an azide derivative (compound B3) in an amountof 1.07 g (yield, 77.7%). Data of the compound B3 IR: (cm-¹, KBr) 2870,2810, 2050, 1490, 1440. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.25-7.35 (1OH, m), 5.69-5.82 (1H, m), 5.35-5.43 (1H, m),4.30-4.74 (4H, m), 3.89 (0.3H, dd, J=5.5, 8.5 Hz), 3.55-3.70 (3.7H, m),1.97-2.10 (2H, m), 1.25-1.36 (22H, m), 0.88 (3H, t, J=6.8 Hz).

(iv) Synthesis of the compound B5

To a solution of the azide (compound B3, 0.45 g) in tetrahydrofuran (10ml) were added a 10% methanolic hydrochloric acid solution (2 ml) andpalladium black (0.25 g). After the reaction vessel was purged withhydrogen, the mixture was stirred at room temperature for 12 hours, andthen filtered through celite. The filtrate was concentrated to give awhite powdery amine (compound B4, 301 mg). Tetrahydrofuran (10 ml),p-nitrophenyl octanoate (260 mg) and triethylamine (0.15 ml) were addedto the amine, the mixture was stirred at 60° C. for 12 ours. Thereaction mixture was concentrated to give a yrup. Purification of thesyrup on a silica gel column (Wako Gel C-200, 50 g) eluting withchloroform-methanol (20:1) afforded an amide derivative (compound B5) inan amount of 166 mg (yield based on the compound B3, 43.6%). Data of thecompound B5 MS: FDMS 429. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.37 (1H, d, J=7.9.Hz), 4.63-4.69 (1H, m), 4.44-4.49 (1H, m),4.25-4.35 (2H, m), 2.46 (2H, dt, J=3.1, 7.9 Hz), 1.78-1.95 (4H, m),1.16-1.59 (34H, m), 0.87 & 0.82 (each 3H, t, J=6.7 Hz).

(v) Synthesis of the compound B6

To a solution of the amide (compound B5, 48 mg) in tetrahydrofuran (1.0ml) were added stannous chloride (75 mg), silver perchlorate (82 mg) andpowdery Molecular Sieves 4A (200 mg), and the mixture was stirred for 30minutes. The mixture was cooled to -10° C., and a solution ofbenzylgalactosyl fluoride (compound A13, 67 mg) in tetrahydrofuran (2.0ml) was added thereto. The mixture was allowed to warm gradually to roomtemperature, stirred for 2 hours, and then filtered through celite. Thesolids removed were washed with a small amount of acetone and combinedwith the filtrate, and then concentrated. Purification on a silica gelcolumn (Wako Gel C-200, 5 g), eluting with hexane-ethyl acetate (3:1),produced a crude α-galactoside (compound B6), which was subjected to thesubsequent reaction.

(vi) Synthesis of the compound 7

To a solution of the α-galactoside (compound B6, 47 mg) in ethyl acetate(1.5 ml) was added palladium black (15 mg). After the reaction vesselwas purged with hydrogen, the mixture was stirred at room temperaturefor 16 hours. The mixture was filtered through celite, and the filtratewas concentrated. Purification on a silica gel column (Wako Gel C-200,2g),eluting with chloroform-methanol (10:1), produced the compound 7 inan amount of 25.1 mg (yield based on the compound B5, 37.9%). Data ofthe compound 7 α!²³ _(D) =+58.20 (pyridine, c=0.56) MS: FDMS 591. IR:(cm⁻¹, KBr) 3300, 2870, 2810, 1640, 1535, 1460, 1060. mp: 155°-157° C.NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.49 (1H, d, J=8.6 Hz), 6.52 (2H, m), 6.42 (1H, m), 6.33 (1H,bs), 6.12 (1H, bd, J=6.7 Hz), 5.46 (1H, d, 15 J=3.7 Hz), 4.73 (1H, m),4.65 (1H, m), 4.53-4.57 (2H, m), 4.40-4.49 (5H, m), 4.36 (1H, dd, J=5.5,10.4 Hz), 4.27 (1H, m), 2.45 (2H, dt, J=5.5, 7.9 Hz), 1.80-1.92 (4H, m),1.18-1.58 (34H, m), 0.87 & 0.81 (each 3H, t, J=6.7 Hz).

¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.2 (d), 73.1 (d), 72.0 (d), 71.7 (d), 71.0 (d),70.8 (d), 70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t),32.1 (t), 31.9 (t), 25 30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.64(t), 29.61 (t), 29.4 (t), 26.6 (t), 26.4 (t), 22.93 (t), 22.86 (t), 14.3(q), 14.2 (q).

Synthesis of the compound 5 (FIG. 7)!

Abbreviations in the above scheme are the same as those in thepreviously described scheme.

(i) Synthesis of the compound B7

To a solution of the azide (compound B3, 3.9 g) in ethyl acetate (50 ml)was added 10% palladium on charcoal (1.2 g). After the reaction vesselwas purged with hydrogen, the mixture was stirred at room temperaturefor 16 hours. The catalyst was filtered off, and the filtrate wasconcentrated and purified on a silica gel column (Wako Gel C-200, 300 g,hexane-acetone (6:1)) to give an amine. (compound B7) in an amount of3.22 g (yield, 86.7%). MS: FDMS 480. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.24-7.35 (1OH, m), 5.79 (0.7H, dt, J=7.3, 11.6 Hz), 5.71 (0.3H, dt, J=6.7, 15.3 Hz), 5.34-5.41 (1H, m), 4.30-4.58 (4H, m), 4.17(0.7H, dd, J=6.7, 9.8 Hz), 3.72 (0.3H, dd, J=6.7, 8.5 Hz), 3.42-3.66(2H, m), 3.06-3.10 (1H, m), 2.01-2.14 (2H, m), 1.26-1.50 (22H, m), 0.88(3H, t, J=6.7.Hz).

(ii) Synthesis of the compound B8

To a solution of the amine (compound B7, 2.22 g) in methylene chloride(50 ml), 2-chloro-1-methylpyridinium iodide (1.88 g) were addedn-tributylamine (1.75 ml) and myristic acid (1.47 g), and the mixturewas heated under reflux and stirred for 2 hours. The reaction mixturewas washed sequentially with a 5% aqueous sodium thiosulfate solutionand brine, and then concentrated. Purification on a silica gel column(Wako Gel C-200, 100 g) eluting with chloroform-acetone (200:1),produced an amide (compound B8) in an amount of 2.41 g (yield, 75.6%).MS: FDMS 691. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.26-7.32 (1OH, m), 5.64-5.73 (2H, m), 5.33-5.41 (1H, m),4.19-4.59 (6H, m), 3.79-3.89 (1H, m), 3.51-3.58 (1H, m), 1.98-2.13 (2H,m), 1.26-1.58 (46H, m), 0.88 (6H, t, J=6.7 Hz).

(iii) Synthesis of the compound B9

To the amide (compound B8, 3.50 g) were added 1-propanol (15 ml),tetrahydrofuran (15 ml), 10% palladium on charcoal (1.2 g) and formicacid (3.0 ml). The mixture was stirred at 45° C. for 16 hours in anitrogen atmosphere. The catalyst was removed by filtration, and thefiltrate was concentrated. Crystallization of the residue fromchloroform-acetone produced a ceramide (compound B9) in an amount of2.08 g (yield, 80.4%). α!²⁴ _(D) =+3.50 (pyridine, c=1.87) MS: FDMS 513.mp: 104°-105° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.35 (1H, d, J=9.2 Hz), 6.36 (1H, t, J=4.9 Hz), 6.24 (1H, d,J=6.1 Hz), 4.62-4.67 (1H, m), 4.46 (1H, dt, J=4.9, 11.0 Hz), 4.25-4.33(2H, m), 2.47 (2H, dt, J=1.8, 7.3 Hz), 1.25-1.95 (50H, m), 0.88 (6H, t,J=6.7 Hz).

(iv) Synthesis of the compound B10

To a solution of the ceramide (compound B9, 1.0 g) in tetrahydrofuran.(30 ml) were added stannous chloride (1.29 g), silver perchlorate (1.41g) and powdery Molecular Sieves 4A (1.5 g), and the mixture was stirredfor 30 minutes. The mixture was cooled to -10° C., and a solution ofbenzylgalactosyl fluoride (compound A13, 1.11 g) in tetrahydrofuran (10ml) was added. The resulting mixture was allowed to warm gradually toroom temperature, stirred for 2 hours, and then filtered through celite.The solids removed were washed with a small amount of acetone, and theextract was combined with the filtrate, and then concentrated andpurified on a silica gel column (Wako Gel C-200, 150 g, hexane-ethylacetate (3:1)) to give an α-galactoside (compound B10) in an amount of646 mg (yield, 32.0%). MS: FDMS 1035. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.23-7.37 (20H, m), 6.49 (1H, d, J=7.9 Hz), 4.92 (1H, d, J=11.3Hz), 4.84 (1H, d, J=12.2 Hz), 4.73-4.78 (3H, m), 4.67 (1H, d, J=11.6Hz), 4.46 (1H, d, J=11.6 Hz), 4.37 (1H, d, J=11.6 Hz), 4.03 (1H, dd,J=3.7, 9.8 Hz), 3.96 (1H, bs), 3.83-3.92 (4H, m), 3.70 (1H, dd, J=3.1,10.4 Hz), 3.47-3.58 (3H, m), 3.40 (1H, d, J=9.8 Hz), 2.12 (2H, dt,J=1.8, 7.9 Hz), 1.25-1.61 (51H, m), 0.88 (6H, t, J=6.7 Hz).

(v) Synthesis of the compound 5

To a solution of the galactoside (compound B10, 1.59 g) intetrahydrofuran (30 ml) was added palladium black (290 mg). After thereaction vessel was purged with hydrogen, the mixture was stirred atroom temperature for 16 hours. The catalyst was removed by filtration,and the filtrate was concentrated. Purification on a silica gel column(Wako Gel C-200, 100 g), eluting with chloroform-methanol (5:1),produced the compound 5 in an amount of 984 mg (yield, 95.0 %). Data ofthe compound 5 α!²⁴ _(D) =+57.80 (pyridine, c=1.69) MS: FDMS 674. IR:(cm⁻¹, KBr) 3400, 3270, 2920, 2850, 1640, 1550, 1465, 1135, 1075, 1045.mp: 159.0°-161.0° C., NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 6.51 (1H, m), 6.44 (1H, m), 6.33 (1H,m), 6.15 (1H, m), 5.45 (1H, d, J=3.7 Hz), 4.73 (1H, m), 4.65 (1H, m),4.40-4.58 (6H, m), 4.36 (1H, dd, J=5.5, 10.0 Hz), 4.28 (1H, m), 2.48(2H, t, J=7.0 Hz), 1.80-1.95 (4H, m), 1.57 (1H, m), 1.18-1.43 (49H, m),0.88 (6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.2 (d), 73.1 (d), 71.9 (d), 71.7 (d), 71.0 (d),70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.02 (t), 29.97 (t), 29.91 (t), 29.87 (t), 29.8(t), 29.7 (t), 29.6 (t), 26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).

(3) Synthetic route C

A specific synthetic route with the use of a sphingosine can beillustrated by the following reaction route scheme. While the reactionroute scheme is illustrated specifically with reference to theaforementioned compounds 1 and 5, the compounds (2-4, 6-8, 14) accordingto the present invention can also be synthesized by applying thismethod. Furthermore, the compounds 15 and 35 having a double bond can besynthesized by conducting deprotection with the use of liquid ammoniaand metallic sodium. Synthesis of the compound 1 (FIG. 8)!

Abbreviations in the above scheme are the same as those in thepreviously described schemes.

(i) Synthesis of the compound C2

To a solution of sphingosine (25 mg) in tetrahydrofuran (1 ml) wereadded p-nitrophenyl tetracosanate (81.8 mg) and 4-dimethylaminopyridine(2.5 mg), and the mixture was stirred at 40° C for 12 hours. The mixturewas evaporated under reduced pressure. Purification on a silica gelcolumn (Wako Gel C-200, 10 g), eluting with chloroform-methanol (4:1),produced an amide (compound C2) in an amount of 23.2 mg (yield, 42.7%).Data of the compound C2 α!²³ _(D) =-11.3° (pyridine, c=1.03) MS: FDMS651. IR: (cm⁻¹, KBr) 3280, 2910, 2840, 1635, 1540, 1465. mp: 87.5°-89.5°C. NMR: ¹ H (500 MHz, CDCl₃ +CD₃ OD (ldrop); 27° C.)

δ (ppm) 5.76 (1H, dt, J=6.7, 15.3 Hz), 5.49 (1H, dd, J=6.7, 15.3 Hz),4.24 (1H, bs), 3.82-3.91 (2H, m), 3.67 (1H, m), 2.21 (2H, t, J=7.6 Hz),1.9-2.1 (2H, m), 1.62 (2H, m), 1.2-1.4 (62H, m), 0.88 (6H, t, J=6.7 Hz).

(ii) Synthesis of the compound C3

To a solution of the amide (compound C2, 33.8 mg) in tetrahydrofuran(1.5 ml) were added stannous chloride (33 mg), silver perchlorate (36mg) and powdered Molecular Sieves 4A (140 mg), and the mixture wasstirred for 30 minutes. The mixture was next cooled to -10° C., asolution of benzylgalactosyl fluoride (compound A13, 28 mg) intetrahydrofuran (0.5 ml) was added to it. The resulting mixture wasallowed to gradually warm to room temperature. After being stirred for 3hours, the mixture was diluted with acetone and filtered through celite,and the filtrate was evaporated under reduced pressure. Purification ona silica gel column (Wako Gel C-200, 10 g) eluting with hexane-ethylacetate (3:1), produced an α-galactoside (compound C3) in an amount of19.7 mg (yield, 32.4%). Data of the compound C3 α!²³ _(D) =+25.10(CHCl₃, c=0.47) MS: FDMS 1173. IR: (cm⁻¹, KBr) 3210, 2920, 2850, 1640,1590, 1545, 1495, 1465, 1450, 1335, 1290, 1110. mp: 63.0°-64.5° C. NMR:¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.23-7.37 (20H, m), 6.40 (1H, d, J=7.9 Hz), 5.65 (1H, m), 5.42(1H, dd, J=6.1, 15.3 Hz), 4.91, 4.85, 4.70, 4.55, 4.47 & 4.38 (each 1H,d, J=11.6 Hz), 4.75 (2H, s), 4.12 (1H, m), 3.95-4.06 (3H, m), 3.79-3.92(3H, m), 3.4-3.71 (3H, m), 2.12 (2H, dt, J=3.4, 7.6 Hz), 1.90-2.01 (3H,m), 1.1-1.6 (63H, m), 0.88 (6H, t, J=6.7 Hz).

(iii) Synthesis of the compound 1

To a solution of the α-galactoside (compound C3, 9.7 mg) intetrahydrofuran (1.0 ml) was added a 5% palladium on barium sulfate (5mg). After the reaction vessel was purged with hydrogen, the mixture wasstirred at room temperature for 16 hours, and then filtered throughcelite. The filtrate was concentrated and purified on a silica gelcolumn (Wako Gel C-200, 10 g, chloroform-methanol (10:1)) to give thecompound 1 in an amount of 3.0 mg (yield, 44.5 mg). Data of the compound1 α!²³ _(D) =+50.00 (pyridine, c=0.26) MS: FDMS 814. IR: (cm⁻¹, KBr)3260, 2910, 2850, 1645, 1545, 1470, 1350, 1125, 1065. mp: 184.5°-186.5°C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 5.46 (1H, d, J=3.7 Hz), 4.74 (1H, m),4.66 (1H, dd, J=3.6, 9.8 Hz), 4.54-4.60 (2H, m), 4.40-4.52 (4H, m), 4.37(1H, dd, J=5.5, 10.4 Hz), 4.29 (1H, m), 2.48 (2H, t, J=7.3 Hz), 1.8-2.0(4H, m), 1.58 (1H, m), 1.20-1.45 (65H, m), 0.881 & 0.877 (each 3H, t,J=7.3 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.2 (d), 73.1 (d), 71.9 (d), 71.7 (d), 71.0 (d),70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.83 (t), 29.76 (t), 29.6 (t),26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q). Synthesis of the compound 5(FIG. 9)!

Abbreviations in the above scheme are the same as those in thepreviously described schemes.

(i) Synthesis of the compound C4

To a solution of sphingosine (75 mg) in tetrahydrofuran (1.5 ml) wereadded p-nitrophenyl myristate (175 mg) and 4-dimethylaminopyridine (7.6mg), and the mixture was stirred at 46° C. for 12 hours. The reactionmixture was concentrated directly and purified on a silica gel column(Wako Gel C-200, 10 g, hexane- acetone (3:1)) to give an amide (compoundC4) in an amount of 112.6 mg (yield, 88.3%). Data of the compound C4α!²³ _(D) =-11.40° (pyridine, c=0.58) MS: FDMS 510. IR: (cm⁻¹, KBr)3300, 2910, 2850, 1640, 1620, 1550, 1470, 1380, 1265, 1240, 1040. mp:96.5°-98.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.) δ (ppm) 8.33 (1H, d,J=8.5 Hz), 6.7 (1H, m), 6.05 (1H, dd, J=6.4, 15.9 Hz), 5.96 (1H, dt,J=6.4, 15.9 Hz), 4.85 (1H, t, J=6.7 Hz), 4.75 (1H, m), 4.47 (1H, dd,J=4.9, 11.0 Hz), 4.30 (1H, dd, J=4.0, 10.7 Hz), 2.47 (2H, t, J=7.6 Hz),2.10 (2H, m), 1.85 (2H, m), 1.39 (4H, m), 1.20-1.33 (38H, m), 0.88 (6H,t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.5 (s), 132.4 (d), 132.3 (d), 73.3 (d), 62.2 (t), 56.9 (d),36.9 (t), 32.7 (t), 32.1 (t), 29.99 (t), 29.96 (t), 29.93 (t), 29.87(t), 29.8 (t), 29.7 (t), 29.61 (t), 29.55 (d), 26.4 (t), 22.9 (t), 14.3(q).

(ii) Synthesis of the compound C5

To a solution of the amide (compound C4, 106.8 mg) in tetrahydrofuran(4.5 ml) was added a powdered Molecular Sieves 4A (400 mg), and themixture was stirred for 10 minutes. Stannous chloride (133 mg) andsilver perchlorate (146 mg) were added, and the mixture was furtherstirred for 30 minutes. The reaction mixture was cooled to -10° C., anda solution of benzylgalactosyl fluoride (compound A13, 113 mg) intetrahydrofuran (1.5 ml) was added thereto. After 30 minutes, it wasallowed to warm to room temperature, stirred for 30 minutes, thendiluted with chloroform-methanol (1:1) and filtered through celite, andthe filtrate was evaporated under reduced pressure. Purification of theresidue on a silica gel column (Wako Gel C-200, 15 g), eluting withhexane-ethyl acetate (5:2), produced an α-galactoside (compound C5) inan amount of 76.0 mg (yield, 35.2%). Data of the compound C5 α!²⁴ _(D)=+32.70 (CHCl₃, c=2.26) MS: FDMS 1033. IR: (cm⁻¹, KBr) 3320, 2920, 2850,1640, 1615, 1545, 1465, 1450, 1350, 1105, 1045. mp: 66.0°-68.0° C. NMR:¹ H (500 MHz, CDCl₃ ; 27° C.) (ppm) 7.25-7.37 (20H, m), 6.40 (1H, d,J=7.9 Hz), 5.66 (1H, dt, J=7.9, 15.3 Hz), 5.42 (1H, dd, J=5.5, 15.3 Hz),4.91, 4.85, 4.70, 4.55, 4.47 & 4.38 (each 1H, d, J=11.6 Hz), 4.752 (2H,s), 4.747 (1H, d, J=4.9 Hz), 4.13 (1H, m), 4.03 (1H, dd, J=3.7, 10.4Hz), 3.95-4.01 (2H, m), 3.79-3.89 (4H, m), 3.69 (1H, dd, J=3.7, 10.3Hz), 3.45-3.55 (2H, m), 2.12 (2H, dt, J=3.7, 7.9 Hz), 1.99 (2H, m), 1.58(2H, m), 1.2-1.4 (42H, m), 0.88 (6H, t, J=7.0 Hz). ¹³ C (125 MHz, CDCl₃; 27° C.)

δ (ppm) 173.3 (s), 138.5 (s), 138.4 (s), 138.0 (s), 137.6 (s), 133.0(d), 129.2 (d), 128.44 (d), 128.41 (d), 128.3 (d), 128.13 (d), 128.10(d), 127.90 (d), 127.86 (d), 127.6 (d), 127.4 (d), 126.1 (d), 99.1 (d),79.2 (d), 75.9 (d), 74.8 (t), 74.4 (d), 74.2 (t), 74.0 (d), 73.6 (t),72.7 (t), 69.8 (d), 69.0 (t), 68.7 (t), 52.8 (d), 36.7 (t), 32.3 (t),31.9 (t), 29.68 (t), 29.65 (t), 29.5 (t), 29.41 (t), 29.36 (t), 29.32(t), 29.26 (t), 25.8 (t), 22.7 (t), 14.1 (q).

(iii) Synthesis of the compound 5

To a solution of the galactoside (compound C5, 7.3 mg) intetrahydrofuran (2.0 ml) was added palladium black (1.5 mg). After thereaction vessel was purged with hydrogen, the mixture was stirred atroom temperature for 16 hours, and then filtered through celite. Thefiltrate was concentrated. Purification on a silica gel column (Wako GelC-200, 2 g), eluting with chloroform-methanol (8:1), produced thecompound 5 in an amount of 4.4 mg (yield, 90.9%).

Data of the compound 5 was the same as those described above.

The compounds other than those described above (1-14) were synthesizedby using appropriate carboxylic acids or combining Wittig's salts havingalkyl groups of a variety of lengths in accordance with the syntheticmethods of the compounds (9, 7, 5, 1) (synthetic routes A-C). Thecompounds 15, 35 and 29 had double bonds unreduced by conducting thereduction at the final stage with liquid ammonia and metallic sodium.Examples of the synthesis of these compounds are illustrated below.

Compound 2

The compound 2 was obtained by reacting the sphingosine C1 withp-nitrophenyl docosanoate in place of p-nitrophenyl tetracosanoate inthe synthesis of the compound 1 and conducting synthesis by applying theroute C.

As an alternative method, the compound 2 was obtained by reacting theamine B4 with p-nitrophenyl docosanoate in place of p-nitrophenyloctanoate in the synthesis of the compound 7 and conducting synthesis byapplying the route B. Data! α!²⁵ _(D) =+50.70 (pyridine, c=0.82) MS:FDMS 787. IR: (cm⁻¹, KBr) 3390, 3220, 2870, 2810, 1635, 1535, 1455,1080, 1055. mp: 147.0°-149.5° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.53 (1H, d, J=8.6 Hz), 5.46 (1H, d, J=3.1 Hz), 4.74 (1H, m),4.66 (1H, m), 4.4-4.6 (6H, m), 4.37 (1H, dd, J=5.8, 10.1 Hz), 4.29 (1H,m), 2.48 (2H, t, J=7.3 Hz), 1.80-1.97 (4H, m), 1.58 (1H, m), 1.20-1.45(61H, m), 0.880 & 0.876 (each 3H, t, J=7.3 Hz). ¹³ C (125 MHz, C₅ D₅ N;27° C.)

δ (ppm) 173.4 (s), 102.2 (d), 73.1 (d), 72.0 (d), 71.7 (d), 71.0 (d),70.6 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.0 (t), 29.95 (t), 29.92 (t), 29.83 (t), 29.76(t), 29.62 (t), 29.61 (t), 26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 3

The compound 3 was obtained by reacting the sphingosine C1 withp-nitrophenyl icosanoate in place of p-nitrophenyl tetracosanoate in thesynthesis of the compound 1 and conducting synthesis by applying theroute C.

As an alternative method, the compound 3 was obtained by reacting. theamine B4 with p-nitrophenyl icosanoate in place of p-nitrophenyloctanoate in the synthesis of the compound 7 and conducting furthersynthesis by applying the route B. Data! α!²⁵ _(D) =+47.3° (pyridine,c=1.76) MS: FDMS 759. IR: (cm⁻¹, KBr) 3390, 3220, 2880, 2810, 1635,1530, 1455, 1080, 1055. mp: 151.5-153.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N;27° C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 5.46 (1H, d, J=4.3 Hz), 4.73 (1H, m),4.66 (1H, dd, J=4.5, 10.1 Hz), 4.4-4.6 (6H, m), 4.37 (1H, dd, J=5.5,10.4 Hz), 4.29 (1H, m), 2.48 .(2H, t, J=7.3 Hz), 1.80-1.97 (4H, m), 1.58(1H, m), 1.20-1.42 (57H, m), 0.879 & 0.876 (each 3H, t, J=7.3 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.1 (d), 73.1 (d), 71.9 (d), 71.6 (d), 71.0 (d),70.5 .(d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.7 (t), 29.6 (t),26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 4

The compound 4 was obtained by reacting the sphingosine C1 withp-nitrophenyl stearate in place of p-nitrophenyl tetracosanoate in thesynthesis of the compound 1 and conducting further synthesis by applyingthe route C.

As an alternative method, the compound 4 was obtained by reacting theamine B4 with p-nitrophenyl stearate in place of p-nitrophenyl octanoatein the synthesis of the compound 7 and conducting further synthesis byapplying the route B. Data! α! ²⁵ _(D) =+55.5° (pyridine, c=0.84) MS:FDMS 731. IR: (cm⁻¹, KBr) 3230, 2940, 2830, 1640, 1540, 1465, 1345,1120, 1090, 1060. mp: 157.5°-159.5° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27°C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 5.46 (1H, d, J=3,7 Hz), 4.73 (1H, m),4.66 (1H, dd, J=3.7, 9.8 Hz), 4.57 (1H, d, J=2.5 Hz), 4.55 (1H, t, J=6.1Hz), 4.40-4.51 (4H, m), 4.37 (1H, dd, J=5.8, 10.7 Hz), 4.29 (1H, m),2.48 (2H, t, J=7.3 Hz), 1.80-1.96 (4H, m), 1.59 (1H, m), 1.2-1.44 (53H,m), 0.88 (6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.1 (d), 73.1 (d), 71.9 (d), 71.7 (d), 71.0 (d),70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.7 (t), 29.6 (t),26.6 (t), 26.4 (t), 22.9 (t), 22.8.(t), 14.3 (q).

Compound 6

The compound 6 was obtained by reacting the sphingosine Cl withp-nitrophenyl decanoate in place of p-nitrophenyl tetracosanoate in thesynthesis of the compound 1 and conducting further synthesis by applyingthe route C.

As an alternative method, the compound 6 was obtained by reacting theamine B4 with p-nitrophenyl decanoate in place of p-nitrophenyloctanoate in the synthesis of the compound 7 and conducting furthersynthesis by applying the route B. Data! α!²⁵ _(D) =+54.8° (pyridine,c=0.93) MS: FDMS 619. IR: (cm⁻¹, KBr) 3245, 2900, 2840, 1635, 1540,1460, 1345, 1120, 1090, 1060. mp: 151.0-154.0° C. NMR: ¹ H (500 MHz, C₅D₅ N; 27° C.)

δ (ppm) 8.52 (1H, d, J=9.2 Hz), 6.14 (1H, m), 5.45 (1H, d, J=3.7 Hz),4.74 (1H, m), 4.65 (1H, dd, J=4.0, 10.1 Hz), 4.57 (1H, d, J=3.4 Hz),4.54 (1H, t, J=5.8 Hz), 4.40-4.50 (4H, m), 4.36 (1H, dd, J=5.5, 11.0Hz), 4.28 (1H, m), 2.47 (2H, dt, J=1.5, 7.6 Hz), 1.80-1.95 (4H, m), 1.57(1H, m), 1.15-1.40 (37H, m), 0.87 & 0.85 (each 3H, t, J=6.7 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.4 (s), 102.1 (d), 73.1 (d), 71.9 (d), 71.6 (d), 71.0 (d),70.5 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.12 (t),32.05 (t), 30.2 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.7 (t),29.61 (t), 29.55 (t), 26.6 (t), 26.4 (t), 22.93 (t), 22.90 (t), 14.3(q).

Compound 8

The compound 8 was obtained by reacting the sphingosine C1 with aceticanhydride in place of p-nitrophenyl tetracosanoate in the synthesis ofthe compound 1 and conducting further synthesis by applying the route C.

As an alternative method, the compound 8 was obtained by reacting theamine B4 with acetic anhydride in place of p-nitrophenyl octanoate inthe synthesis of the compound 7 and conducting further synthesis byapplying the route B. Data! α!²⁵ _(D) =+74.3° (pyridine, c=1.36) MS:FDMS 507. IR: (cm⁻¹, KBr) 3230, 2890, 2830, 1630, 1540, 1465, 1370,1140. mp: 171.0°-172.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.63 (1H, d, J=8.6 Hz), 6.1 (2H, m), 5.43 (1H, d, J=3.7 Hz),4.70 (1H, m), 4.64 (1H, dd, J=4.0, 10.1 Hz), 4.55 (1H, d, J=2.4 Hz),4.52 (1H, t, J=6.1 Hz), 4.46 (1H, dd, J=3.7, 10.4 Hz), 4.38-4.44 (3H,m), 4.31 (1H, dd, J=6.1, 10.4 Hz), 4.26 (1H, m), 2.13 (3H, s), 1.77-1.90(3H, m), 1.55 (1H, m), 1.20-1.40 (24H, m), 0.87 (3H, t, J=7.0 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 170.3 (s), 102.0 (d), 73.0 (d), 71.9 (d), 71.6 (d), 70.9 (d),70.5 (d), 69.4 (t), 62.6 (t), 55.0 (d), 35.0 (t), 32.1 (t), 30.1 (t),30.04 (t), 29.97 (t), 29.9 (t), 29.6 (t), 26.6 (t), 23.3 (q), 22.9 (t),14.3 (q).

Compound 10

In the synthesis of the compound 7, the aldehyde A2 was reacted withdodecanetriphenylphosphonium bromide in place oftetradecanetriphenylphosphonium bromide. Next, the amine obtained in thereduction was reacted with p-nitrophenyl myristate in place ofp-nitrophenyl octanoate, and synthesis was further conducted by applyingthe route B to give the compound 10. Data! α!²⁴ _(D) =+74.30 (pyridine,c=0.35) MS: FDMS 646. IR: (cm⁻¹, KBr) 3250, 2900, 2830, 1640, 1540,1460, 1120, 1085, 1060. mp: 153.5°-156.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N;27° C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 6.1 (1H, m), 5.47 (1H, d, J=3.7 Hz),4.75 (1H, m), 4.67 (1H, dd, J=3.7, 9.8 Hz), 4.34-4.60 (7H, m), 4.29 (1H,m), 2.48 (2H, dt, J=1.2, 7.3 Hz), 1.80-1.95 (4H, m), 1.58 (1H, m),1.20-1.42 (41H, m), 0.87 (6H, t, J=6.8 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27°C.)

δ (ppm) 173.4 (s), 102.1 (d), 73.1 (d), 72.0 (d), 71.7 (d), 71.0 (d),70.6 (d), 69.7 (t), 62.7 (t), 54.9 (d), 36.8 (t), 35.1 (t), 32.1 (t),30.2 (t), 30.1 (t), 30.00 (t), 29.97 (t), 29.9 (t), 29.8 (t), 29.7 (t),29.6 (t), 26.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 11

In the synthesis of the compound 10, the (2S,3S)-aldehyde was used inplace of the aldehyde A2, and the synthesis was conducted by applyingthe route B to give the compound 11. Data! α!²⁴ _(D) =+62.00 (pyridine,c=0.50) MS: FDMS 646. IR: (cm⁻¹, KBr) 3290, 2910, 2840, 1640, 1615,1540, 1465, 1140, 1050. mp: 145.0°-147.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N;27° C.)

δ (ppm) 8.40 (1H, d, J=8.5 Hz), 6.28 (1H, m), 5.47 (1H, d, J=3.7 Hz),4.66-4.76 (3H, m), 4.10-4.62 (7H, m), 2.48 (2H, dt, J=1.8, 7.3 Hz),1.80-2.00 (3H, m), 1.70 (1H, m), 1.57 (1H, m), 1.20-1.42 (41H, m), 0.88(6H, t, J=6.7 Hz).

Compound 12

In the synthesis of the compound 10, the (2S,3R)-aldehyde was used inplace of the aldehyde A2, and the synthesis was conducted by applyingthe route B to give the compound 12. Data! α!²³ _(D) =+52.50 (pyridine,c=0.75) MS: FDMS 646. IR: (cm⁻¹, KBr) 3480, 3240, 2910, 2840, 1630,1560, 1460, 1070, 1005. mp: 148.5°-152.5° C. NMR: ¹ H (500 MHz, C₅ D₅ N;27° C.)

δ (ppm) 8.10 (1H, d, J=8.6 Hz), 5.46 (1H, d, J=3.7 Hz), 4.79 (1H, m),4.66 (1H, dd, J=3.7, 9.8 Hz), 4.34-4.56 (7H, m), 4.12 (1H, t, J=6.1 Hz),4.07 (1H, dd, J=6.1, 9.8 Hz), 2.49 (2H, t, J=6.5 Hz), 1.75-1.92 (3H, m),1.69 (1H, m), 1.55 (1H, m), 1.20-1.42 (41H, m), 0.88 (6H, t, J=6.7 Hz).¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.6 (s), 101.4 (d), 73.0 (d), 71.8 (d), 71.1 (d), 70.6 (d),70.4 (d), 69.8 (t),. 62.8 (t), 53.1 (d), 36.8 (t), 35.3 (t), 32.1 (t),30.2 (t), 30.0 (t), 29.93 (t), 29.89 (t), 29.8 (t), 29.7 (t), 29.6 (t),26.6 (t), 26.5 (t), 22.9 (t), 14.3 (q).

Compound 13

In the synthesis of the compound 10, the (2R,3S)-aldehyde was used inplace of the aldehyde A2, and the synthesis was conducted by applyingthe route B to give the compound 13. Data! α!²⁴ _(D) =+80.70 (pyridine,c=0.27) MS: FDMS 646. IR: (cm¹, KBr) 3300, 2900, 2820, 1635, 1520, 1460,1065, 1005. mp: 149.0°-150.5° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.04 (1H, d, J=8.6 Hz), 6.4 (1H, m), 5.49 (1H, d, J=3.7 Hz),4.80 (1H, m), 4.68 (1H, dd, J=3.7, 9.8 Hz), 4.65 (1H, bd, J=2.4 Hz),4.36-4.58 (6H, m), 4.16 (1H, dd, J=6.7, 10.4 Hz), 2.50 (2H, t, J=7.3Hz), 1.75-1.92 (3H, m), 1.69 (1H, m), 1.53 (1H, m), 1.20-1.42 (41H, m),0.88 (6H, t, J=7.0 Hz).

Compound 14

The compound 14 was obtained by reacting the sphingosine Cl withp-nitrophenyl (R)-2-acertoxytetracosanoate in place of p-nitrophenyltetracosanoate in the synthesis of the compound 1 and further conductingthe synthesis by applying the route C.

As an alternative method, the compound 14 was obtained by reacting theamine B4 with p-nitrophenyl (R)-2-acetoxytetracosanoate in place ofp-nitrophenyl octanoate in the synthesis of the compound 7 andconducting further synthesis by applying the route B. Data! MS: FDMS831. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.45 (1H, d, J=9.2 Hz), 5.44 (1H, d, J=3.7 Hz), 4.71 (1H, m),4.64 (2H,r m), 4.53 (3H, m), 4.40 (3H, m), 4.25 (1H, m), 2.22 (1H,r m),2.09 (1H, m), 1.70-1.95 (4H, m), 1.54 (1H, m), 1.2-1.45 (63H, m), 0.884& 0.876 (each 3H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.1 (s), 101.9 (d), 73.2 (d), 72.4 (d), 71.7 (d), 71.0 (d),70.5 (d), 69.4 (t), 62.7 (t), 54.1 (d), 35.6 (t), 35.2 (t), 32.1 (t),30.3 (t), 30.04 (t), 29.97 (t), 29.9 (t), 29.64 (t), 29.61 (t), 26.5(t), 25.8 (t), 22.9 (t), 14.3 (q).

Compound 15

The compound 15 was obtained by reacting the sphingosine Cl withp-nitrophenyl stearate in place of p-nitrophenyl tetracosanoate in thesynthesis of the compound 1 and further conducting the synthesis byapplying the route C. The compound 15 as the deprotected derivative wasobtained by conducting the deprotection at the final step by wetting theraw material with a small amount of tetrahydrofuran and adding theretoliquid ammonia and next metallic sodium. Data! α!²⁵ _(D) =+41.40(pyridine, c=0.14) MS: FDMS 729. IR: (cm⁻¹, KBr) 3230, 2880, 2810, 1630,1535, 1460, 1375, 1065, 1040. mp: 169.0°-172.0° C. NMR: ¹ H (500 MHz, C₅D₅ N; 27° C.)

δ (ppm) 8.50 (1H, d, J=8.6 Hz), 6.01 (2H, bs), 5.47 (1H, d, J=3.7 Hz),4.86 (2H, m), 4.67 (1H, dd, J=4.0, 10.1 Hz), 4.59 (1H, d, J=2.4 Hz),4.54 (1H, t, J=5.8 Hz), 4.40-4.50 (5H, m), 4.37 (1H, m), 2.46 (2H, dt,J=3.1, 7.6 Hz), 2.09 (2H, bs), 1.84 (2H, m), 1.15-1.45 (50H, m), 0.88(6H, t, J=6.4 Hz).

Compound 29

The synthesis was conducted by reacting the amine A7 with oleic acid inplace of tetracosanoic acid in the synthesis of the compound 9 andfurther continuing the synthesis by applying the route C. The compound29 as the deprotected derivative was obtained by conducting thedeprotection in the final step by wetting the raw material with a smallamount of tetrahydrofuran and then adding thereto liquid ammonia andmetallic sodium. Data! α!²⁴ _(D) =+46.60 (pyridine, c=0.17) MS: FDMS728. IR: (cm⁻¹, KBr) 3400, 2900, 2820, 1640, 1540, 1460, 1060. mp:134°-136° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.52 (1H, d, J=8.6 Hz), 6.54 (1H, bs), 6.45 (1H, bs), 6.35 (1H,bs), 6.15 (1H, bs), 5.44 (3H, m), 4.73 (1H, m), 4.66 (1H, dd, J=3.7, 9.8Hz), 4.33-4.58 (7H, m), 4.27 (1H, m), 2.45 (2H, m), 2.06 (3H, m),1.75-1.92 (2H, m), 1.55 (1H, m), 1.14-1.42 (48H, m), 0.84 (6H, m). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.3 (s), 130.1 (d), 130.1 (d), 102.0 (d), 73.0 (d), 71.8 (d),71.6 (d), 70.9 (d), 70.4 (d), 69.6 (t), 62.6 (t), 54.9 (d), 36.7 (t),35.0 (t), 32.0 (t), 32.0 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t),29.7 (t), 29.6 (t), 29.6 (t), 29.5 (t), 29.5 (t), 29.4 (t), 27.4 (t),26.5 (t), 26.3 (t), 22.9 (t), 14.2 (q).

Compound 32

The synthesis was conducted by reacting the sphingosine Cl withp-nitrophenyl myristate in place of p-nitrophenyl tetracosanoate in thesynthesis of the compound 1 and further by applying the route C. Thecompound 32 as the deprotected derivative was obtained by conducting thedeprotection at the final step by wetting the raw material with a smallamount of tetrahydrofuran and then adding thereto liquid ammonia andmetallic sodium. Data! α!²⁴ _(D) =+48.90 (pyridine, c=0.45) MS: FDMS673. IR: (cm⁻¹, KBr) 3320, 2920, 2855, 1640, 1545, 1470, 1345, 1150. mp:158.0°-160.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.46 (1H, d, J=7.3 Hz), 6.59 (1H, m), 6.41 (1H, m), 6.33 (1H,m), 6.00 (2H, bs), 5.46 (1H, d, J=3.7 Hz), 4.85 (2H, m), 4.65 (1H, dd,J=3.7, 9.8 Hz), 4.58 (1H, m), 4.53 (1H, t, J=6.1 Hz), 4.40-4.50 (4H, m),4.35 (1H, dd, J=5.2, 10.1 Hz), 2.45 (2H, dt, J=3.1, 7.3 Hz), 2.08 (2H,m), 1.84 (2H, m), 1.37 (4H, m), 1.20-1.32 (38H, m), 0.88 (6H, t, J=6.7Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.5 (s), 132.4 (d), 132.0 (d), 102.1 (d), 73.0 (d), 71.7 (d),70.9 (d), 70.6 (d), 69.4 (t), 62.7 (t), 55.1 (d), 36.8 (t), 32.7 (t),32.1 (t), 30.01 (t), 29.99 (t), 29.96 (t), 29.63 (t), 29.87 (t), 29.83(t), 29.76 (t), 29.73 (t), 29.6 (t), 26.4 (t), 22.9 (t), 14.3 (q). (4)Synthetic route D

The specific method for synthesizing a compound having a hydroxyl groupat C-4 of the long chain base in formula (A) can be illustrated by thefollowing reaction route scheme. Although the reaction route schemespecifically illustrates the method with reference to the compound 22,the compounds according to the present invention including 16-34 exceptfor 22 and 29 can also be synthesized by applying the method (synthesisof the compound 22 (FIGS. 10a-10c)).

In the aforementioned scheme, the following abbreviations are used:EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The other abbreviations are the same as those in the previous reactionschemes. α!²⁴ _(D) =+48.90 (pyridine, c=0.45) MS: FDMS 673. IR: (cm⁻¹,KBr) 3320, 2920, 2855, 1640, 1545, 1470, 1345, 1150. mp: 158.0°-160.0°C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.46 (1H, d, J=7.3 Hz), 6.59 (1H, m), 6.41 (1H, m), 6.33 (1H,m), 6.00 (2H, bs), 5.46 (1H, d, J=3.7 Hz), 4.85 (2H, m), 4.65 (1H, dd,J=3.7, 9.8 Hz), 4.58 (1H, m), 4.53 (1H, t, J=6.1 Hz), 4.40-4.50 (4H, m),4.35 (1H, dd, J=5.2, 10.1 Hz), 2.45 (2H, dt, J=3.1, 7.3 Hz), 2.08 (2H,m), 1.84 (2H, m), 1.37 (4H, m), 1.20-1.32 (38H, m), 0.88 (6H, t, J=6.7Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.5 (s), 132.4 (d), 132.0 (d), 102.1 (d), 73.0 (d), 71.7 (d),70.9 (d), 70.6 (d), 69.4 (t), 62.7 (t), 55.1 (d), 36.8 (t), 32.7 (t),32.1 (t), 30.01 (t), 29.99 (t), 29.96 (t), 29.63 (t), 29.87 (t), 3529.83 (t), 29.76 (t), 29.73 (t), 29.6 (t), 26.4 (t), 22.9 (t), 14.3 (q).(4) Synthetic route D

The specific method for synthesizing a compound having a hydroxyl groupat C-4 of the long chain base in formula (A) can be illustrated by thefollowing reaction route scheme. Although the reaction route schemespecifically illustrates the method with reference to the compound 22,the compounds according to the present invention including 16-34 exceptfor 22 and 29 can also be synthesized by applying the method (synthesisof the compound 22 (FIGS. 10a-10c)).

In the aforementioned scheme, the following abbreviations are used:EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The other abbreviations are the same as those in the previous reactionschemes.

(i) Synthesis of the compound D1

The compound D1 can be synthesized by applying the method described inAgricultural and Biological Chemistry, 54 (3), 663-667, 1990.

(ii) Synthesis of the compound D3

To the Wittig's salt (compound D2, 32.07 g) was added tetrahydrofuran(40 ml), and the reaction vessel was purged with argon. A 2N solution ofn-butyl lithium in hexane (30 ml) was added, and the mixture was stirredfor 15 minutes. A solution of the aldehyde (compound D1, 13.18 g) intetrahydrofuran (20 ml) was added dropwise to the mixture, which wasthen allowed to warm to room temperature and stirred for 15 hours. Tothe reaction mixture were added methanol (3 ml) followed by 20% aqueousmethanol (300 ml), and the mixture was extracted thrice with n-hexane.The extracts were washed with brine and concentrated. Purification on asilica gel column (Wako Gel C-200, 400 g), eluting with hexane-ethylacetate (9:1), produced an alcohol (compound D3) in an amount of 9.31 g(yield, 51.9%). Data of the compound D3 α!²⁴ _(D) =+38.20° (CHCl₃,c=1.0) MS: FDMS 573, 301. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.20-7.35 (15H, m), 5.72 (1H, m), 5.46 (1H, bt, J=9.2 Hz), 4.68(1H, d, J=11.2 Hz), 4.60 (1H, d, J=11.7 Hz), 4.47-4.52 (3H, m), 4.44(1H, dd, J=5.5, 9.8 Hz), 4.33 (1H, d, J=11.7 Hz), 4.08 (1H, m), 3.56(1H, dd, J=2.4, 5.5 Hz), 3.51 (2H, d, J=6.1 Hz), 3.01 (1H, d, J=5.5 Hz),1.85-2.01 (2H, m), 1.17-1.36 (18H, m), 0.88 (3H, t, J=6.7 Hz).

(iii) Synthesis of the compound D4

To a solution of the alcohol (compound D3, 9.31 g) in tetrahydrofuran(30 ml) was added 10% palladium on charcoal (0.53 g). After the reactionvessel was purged with hydrogen, the mixture was stirred at roomtemperature for 15 hours, and then filtered through celite. The filtratewas concentrated to give a reduced product (compound D4) in an amount of9.34 g (yield, quantitatively). Data of the compound D4 α!²⁴ _(D)=-35.10 (CHCl₃, c=0.5) MS: FDMS 575. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)δ (ppm) 7.22-7.34 (15H, m), 4.69 (1H, d, J=11.6 Hz), 4.65 (1H, d, J=11.6Hz), 4.55 (1H, d, J=11.0 Hz), 4.52 (1H, d, J=ll.6 Hz), 4.50 (1H, d,J=11.0 Hz), 4.48 (1H, d, J=12.2 Hz), 4.04 (1H, m), 3.68 (1H, m), 3.61(1H, m), 3.54 (2H, m), 3.17 (l,. d, J=4.9 Hz), 1.85 (3H, m), 1.65 (2H,m), 1.56 (1H, m), 1.41 (1H, m), 1.16-1.35 (17H, m), 0.88 (3H, t, J=7.3Hz).

(iv) Synthesis of the compound D5

To a solution of the reduced product (compound D4, 9.34 g) in pyridine(70 ml) was added methanesulfonyl chloride (2.5 ml), and the mixture wasstirred at room temperature for 2 hours, and then concentrated. Afterthe residual acid chloride was distilled azeotropically with toluene,the residue was taken into diethyl ether and washed with brine. Theorganic layer was concentrated and purified on a silica gel column (WakoGel C-200, 500 g, hexane-ethyl acetate (9:1)) to give a mesyl derivative(compound D5) in an amount of 9.74 g (yield, 91.8%). Data of thecompound D5 α!²⁴ _(D) =+6.50 (CHCl₃, c=1.0) MS: FDMS 653. NMR: ¹ H (500MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.25-7.38 (15H, m), 4.91 (1H, dt, J=3.9, 5.6 Hz), 4.76 (1H, d,J=11.2 Hz), 4.62 (1H, d, J=11.2 Hz), 4.58 (1H, d, J=11.5 Hz), 4.55 (1H,d, J=11.7 Hz), 4.48 (1H, d, J=11.2 Hz), 4.48 (1H, d, J=11.7 Hz), 3.89(1H, t, J=4.9 Hz), 3.67-3.76 (2H, m), 3.61 (1H, m), 2.91 (3H, s), 1.72(1H, m), 1.54 (1H, m), 1.41 (1H, m), 1.16-1.35 (21H, m), 0.88 (3H, t,J=7.3 Hz).

(v) Synthesis of the compound D6

To the solution of the mesyl derivative (compound D5, 9.74 g) indimethylformamide (100 ml) was added sodium azide (9.70 g), and themixture was stirred at 120° C. for 16 hours, then concentrated, takeninto ethyl acetate and washed with water and brine. The organic layerwas concentrated and purified on a silica gel column (Wako Gel C-200,200 g, hexane-ethyl acetate (98:2)) to give an azide derivative(compound D6) in an amount of 6.75 g (yield, 75.4%). Data of thecompound D6 α!²⁴ _(D) =+8.20 (CHCl₃, c=1.0) MS: FDMS 600, 573, 450. NMR:¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.25-7.40 (15H, m), 4.69 (1H, d, J=11.2 Hz), 4.60 (1H, d, J=11.2Hz), 4.55 (1H, d, J=11.2 Hz), 4.48-4.53 (3H, m), 3.75-3.81 (2H, m),3.65-3.72 (2H, m), 3.60 (1H, dt, J=3.7, 7.3 Hz), 1.66 (1H, m), 1.56 (1H,m), 1.41 (1H, m), 1.19-1.36 (21H, m), 0.88 (3H, t, J=6.7 Hz).

(vi) Synthesis of the compound D7

To the solution of the azide derivative (compound

D6, 605.5 mg) in tetrahydrofuran (6 ml) was added 10% palladium oncharcoal (60 mg). After the reaction vessel was purged with hydrogen,the mixture was stirred at room temperature for 15 hours, filteredthrough celite, and the filtrate was concentrated and purified on asilica gel column (Wako Gel C-200, 30 g, hexane-ethyl acetate (7:3)) togive an amine (compound D7) in an amount of 459.9 mg (yield, 79.4%).Data of the compound D7 α!²⁴ _(D) =-7.0° (CHCl₃ c=0.5) MS: FDMS 574.NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.23-7.36 (15H, m), 4.74 (1H, d, J=11.2 Hz), 4.63 (1H, d, J=11.5Hz), 4.53 (1H, d, J=11.5 Hz), 4.52 (1H, d, J=11.5 Hz), 4.49 (2H, d,J=1.8 Hz), 3.71 (2H, m), 3.57 (1H, dd, J=3.7, 6.7 Hz), 3.49 (1H, m),3.16 (1H, m), 1.82 (1H, m), 1.69 (1H, m), 1.58 (1H, m), 1.49 (1H, m),1.20-1.35 (20H, bs), 0.88 (3H, t, J=7.3 Hz).

(vii) Synthesis of the compound D8

(R)-2-Acetoxytetracosanoic acid (compound D8) is obtained, for example,by reacting (R)-2-α-hydroxytetracosanoic acid which is synthesized byapplying the method described in Agricultural and Biological Chemistry,54 (12), 3337-3338, 1990 with acetic anhydride in pyridine. Data of thecompound D8 α!²⁰ _(D) =+8.50 (CHCl₃, c=1.0)

(viii) Synthesis of the compound D9

The amine (compound D7, 153.3 mg) and (R)-2-acetoxytetracosanoic acid(compound D8, 113.8 mg) were dissolved in tetrahydrofuran (4 ml), and2-ethoxy-L-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 99.0 mg) was addedto the solution. The mixture was stirred at room temperature for 60hours, then concentrated and purified on a silica gel column (Wako GelC-200, 10 g, hexane-ethyl acetate (9:1)) to give a benzylceramide(compound D9) in an amount of 205.6 mg (yield, 78.3%). Data of thecompound D9 α!²³ _(D) =+2.10 (CHCl₃, c=0.6) MS: FDMS 983. NMR: ¹ H (500MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.22-7.36 (15H, m), 6.50 (1H, d, J=9.2 Hz), 5.05 (1H, dd, J=4.9,7.3 Hz), 4.82 (1H, d, J=11.6 Hz), 4.62 (1H, d, J=11.6 Hz), 4.55 (1H, d,J=11.6 Hz), 15 4.52 (1H, d, J=11.6 Hz), 4.42 (2H, s), 4.23 (1H, m), 3.84(2H, m), 3.51 (1H, m), 3.48 (1H, dd, J=3.7, 9.8 Hz), 1.98 (3H, s),1.60-1.82 (2H, m), 1.50 (1H, m), 1.20-1.35 (63H, m), 0.88 (6H, t, J=7.3Hz).

(ix) Synthesis of the compound D10

To the solution of the benzylceramide (compound D9, 317.7 mg) intetrahydrofuran-n-propanol (1:1) (6 ml) were added 10% palladium oncharcoal (167.4 mg) and formic acid (0.6 ml). After the reaction vesselwas purged with hydrogen, the mixture was stirred at 40° C. for 5 hours.The reaction mixture was diluted with chloroform (10 ml) and filteredthrough celite, and the filtrate was concentrated. Purification on asilica gel column (Wako Gel C-200, 15 g), eluting withchloroform-methanol (98:2), produced a ceramide (compound D10) in anamount 30 of 191.6 mg (yield, 83.2%). Data of the compound D10 α!²³ _(D)=+6.0° (CHCl₃, c=0.1) MS: FDMS 713. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.63 (1H, d, J=8.5 Hz), 6.56 (2H, m), 6.13 (1H, bd, J=5.7 Hz),5.54 (1H, dd, J=5.5, 7.3 Hz), 5.07 (1H, m), 4.47 (1H, m), 4.43 (1H, m),4.38 (1H, m), 4.28 (1H, m), 2.20 (1H, m), 2.07 (2H, m), 2.04 (3H, s),1.90 (2H, m), 1.68 (1H, m), 1.15-1.60 (60H, m), 0.85 (6H, t, J=6.7 Hz).

(x) Synthesis of the compound D11

To the solution of the ceramide (compound D10, 99.7 mg) in pyridine (3ml) were added triphenylmethyl chloride (390.3 mg) and4-dimethylaminopyridine (5.0 mg), and the mixture was stirred at 60° C.for 3 hours. After dilution with chloroform (30 ml), the mixture waswashed with brine and concentrated. Purification on a silica gel column(Wako Gel C-200, 5 g), eluting with chloroform, produced a tritylderivative (compound D11) in an amount of 111.7 mg (yield, 83.6%). Dataof the compound D11 α!²³ _(D) =-13.3° (CHCl₃, c=0.1) NMR: ¹ H (500 MHz,CDCl₃ ; 27° C.) (ppm) 7.21-7.40 (15H, m), 6.89 (1H, d, J=8.6 Hz), 5.21(1H, dd, J=5.1, 6.6 Hz), 4.27 (1H, m), 3.60 (1H, m), 3.43 (1H, dd,J=3.2, 7.1 Hz), 3.36 (1H, dd, J=4.2, 7.1 Hz), 3.34 (1H, m), 3.01 (1H,m), 2.08 (1H, m), 2.05 (3H, s), 1.85 (1H, m), 1.75 (1H, m), 1.68 (1H,m), 1.10-1.50 (62H, m), 0.88 (6H, t, J=7.3 Hz).

(xi) Synthesis of the compound D12

To the solution of the trityl derivative (compound D11, 166.5 mg) inpyridine (3 ml) were added benzoyl chloride (0.18 ml) and4-dimethylaminopyridine (5.0 mg). After stirring at room temperature for36 hours, the mixture was diluted with brine, extracted with chloroformand concentrated. Purification on a silica gel column (Wako Gel C-200,15 g), eluting with hexane-ethyl acetate (95:5), produced a benzoylderivative (compound D12) in an amount of 193.9 mg (yield, 95.6%). Dataof the compound D12 α!²³ _(D) =+7.3° (CHCl₃, c=0.5) MS: FDMS 1162, 920.NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.04-8.16 (25H, m), 5.91 (1H, dd, J=2.4, 9.0 Hz), 5.45 (1H, dt,J=2.9, 9.8 Hz), 5.37 (1H, t, J=7.3 Hz), 4.68 (1H, m), 3.34 (1H, dd,J=3.7, 9.8 Hz), 3.26 (1H, dd, J=2.9, 9.8 Hz), 2.02 (3H, s), 1.12-2.02(66H, m), 0.87 (6H, m).

(xii) Synthesis of the compound D13

To the solution of benzoyl derivative (compound D12, 193.9 mg) in asolution of methylene chloride-methanol (2:1) (3 ml) was addedp-toluenesulfonic acid monohydrate (63.4 mg). After being stirred atroom temperature for 1.5 hours, the mixture was concentrated. Theresidue was dissolved in ethyl acetate and washed with aqueous sodiumhydrogen carbonate and brine, and then concentrated. Purification on asilica gel column (Wako Gel C-200, 15 g), eluting with hexane-ethylacetate (8:2), produced an alcohol (compound D13) in an amount of 113.1mg (yield, 73.7%). Data of the compound D13 α!²³ _(D) =+27.30 (CHCl₃,c=0.1) MS: FDMS 921. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 8.06 (2H, d, J=7.3 Hz), 7.96 (2H, d, J=7.3 Hz), 7.64 (1H, t,J=7.3 Hz), 7.54 (1H, t, J=7.6 Hz), 7.50 (2H, t, J=7.9 Hz), 7.39 (2H, t,J=7.9 Hz), 7.06 (1H, d, J=9.2 Hz), 5.48 (1H, dd, J=2.4, 9.1 Hz), 5.38(1H, dt, J=3.1, 9.8 Hz), 5.19 (1H, t, J=6.1 Hz), 4.37 (1H, m), 3.57-3.68(2H, m), 2.20 (3H, s), 2.02 (2H, m), 1.92 (2H, m), 1.16-1.50 (62H, m),0.88 (6H, m).

(xiii) Synthesis of the compound D14

To the solution of the alcohol (compound D13, 113.1 mg) intetrahydrofuran (2 ml) were added stannous chloride (54.8 mg), silverperchlorate (59.9 mg) and powdered Molecular Sieves 4A (500 mg), and themixture was stirred at room temperature for 30 minutes. After themixture was cooled to -10° C., a solution of benzylgalactosyl fluoride(compound A13, 313.4 mg) in tetrahydrofuran (2 ml) was added. Theresulting mixture was allowed to warm to room temperature, stirred for 2hours, then diluted with acetone, and filtered through celite. Thefiltrate was evaporated under reduced pressure, and the residue wassuspended in ethyl acetate, washed with brine and concentrated.Purification on a silica gel column (Wako Gel C-200, 10 g) eluting withhexane-ethyl acetate (19:1) produced an α-galactoside (compound D14) inan amount of 148.0 mg (yield; 83.5%). Data of the compound D14 α!²³ _(D)=+21.00 (CHCl₃, c=0.1) MS: FDMS 1443. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 8.03 (2H, d, J=7.9 Hz), 7.90 (2H, d, J=7.9 Hz), 7.73 (1H, d,J=8.3 Hz), 7.59 (1H, t, J=6.4 Hz), 7.50 (1H, t, J=6.4 Hz), 7.45 (2H, t,J=7.6 Hz), 7.15-7.40 (22H, m), 5.78 (1H, dd, J=2.6, 9.8 Hz), 5.40 (1H,m), 5.10 (1H, dd, J=5.2, 7.6 Hz), 4.88 (1H, d, J=11.3 Hz), 4.53-4.76(7H, m), 4.48 (1H, d, J=11.8 Hz), 4.40 (1H, d, J=11.8 Hz), 4.09 (1H, t,J=7.2 Hz), 3.99 (1H, dd, J=3.3, 10.4 Hz), 3.93 (1H, m), 3.90 (1H, m),3.82 (1H, dd, J=2.4, 9.8 Hz), 3.59 (1H, dd, J=2.3, 12.1 Hz), 3.53 (1H,dd, J=6.4, 8.9 Hz), 3.45 (1H, dd, J=6.7, 9.2 Hz), 2.44 (1H, bs), 2.02(3H, s), 1.89 (3H, m), 1.40 (2H, m), 1.10-1.35 (61H, m), 0.88 (6H, m).

(xiv) Synthesis of the compound D15

To the solution of the α-galactoside (compound D14, 147.1 mg) in ethylacetate (3 ml) was added palladium black (15 mg). After the reactionvessel was purged with hydrogen and the mixture was stirred at roomtemperature for 4 hours, filtered through celite, and the filtrate wasconcentrated to give a tetraol (compound D15) in an amount of 106.6 mg(yield, 96.6%). Data of the compound D15 α!²³ _(D) =+26.00 (CHCl₃,c=0.1) MS: FDMS 1083, 921. NMR: ¹ H (500 MHz, CDCl₃ ; 27° C.)

δ (ppm) 7.99 (2H, d, J=7.9 Hz), 7.90 (2H, d, J=7.9 Hz), 7.75 (1H, d,J=8.3 Hz), 7.60 (1H, t, J=6.4 Hz), 7.53 (1H, t, J=6.4 Hz), 7.48 (2H, t,J=7.6 Hz), 7.38 (2H, t, J=7.6 Hz), 5.78 (1H, dd, J=2.4, 9.8 Hz), 5.26(1H, m), 5.07 (1H, t, J=6.7 Hz), 4.70 (1H, d, J=3.7 Hz), 4.57 (1H, m),3.98 (1H, bs), 3.90 (1H,-m), 3.80-3.90 (3H, m), 3.78 (1H, m), 3.70 (1H,m), 3.65 (1H, bd, J=10.4 Hz), 3.46 (2H, m), 3.13 (1H, bs), 2.78 (1H, m),2.18 (3H, s), 1.81-1.95 (4H, m), 1.41 (2H, m), 1.16-1.35 (60H, m), 0.88(6H, m).

(xv) Synthesis of the compound 22

To the solution of the tetraol (compound D15, 105.5 mg) in methanol (5ml) was added slowly a 1N methanolic sodium methoxide solution (2 ml),and the mixture was stirred at room temperature for 30 minutes. A cationexchange resin (Dowex 50W, X8, manufactured by The Dow Chemical Company)was added to neutralize the mixture, and the resulting mixture wasfiltered. The solids removed were washed thoroughly with achloroform-methanol (1:1) solution. The extract was combined with thefiltrate, and concentrated. Purification on a silica gel column (WakoGel C-200, 5 g) eluting with chloroform-methanol-water (90:10:1)produced a cerebroside (compound 22) in an amount of 66.7 mg (yield,82.2%). Data of the compound 22 α!²³ _(D=+) 47.40 (Pyridine, c=4.0) MS:FDMS 833. 35 IR: (cm⁻¹, KBr) 3400, 2950, 2870, 1645, 1535, 1475, 1080mp: 202°-204° C. NMR: ¹ H (500 MHz, C₅ D₅ N: 27° C.)

δ (ppm) 8.48 (1H, d, J=9.2 Hz), 7.53 (1H, d, J=4.9 Hz), 7.00 (1H, bs),6.67 (1H, d, J=6.7 Hz), 6.63 (1H, bs), 6.51 (1H, bs), 6.28 (1H, bs),6.07 (1H, d, J=5.5 Hz), 5.57 (1H, d, J=3.7 Hz), 5.26 (1H, m), 4.62 (2H,m), 4.57 (1H, m), 4.51 (1H, bs), 4.46 (2H, m), 4.28-4.40 (4H, m) 4.25(1H, m), 2.27 (1H, m), 2.17 (1H, m), 1.98 (1H, m), 1.87 (2H, m), 1.73(1H, m), 1.66 (2H, m), 1.16-1.46 (58H, m), 0.85 (6H, t, J=6.1 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.5 (d), 73.0 (d), 72.3 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.4 (d), 35.5 (t),34.4 (t), 32.1 (t), 30.3 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t),29.5 (t), 26.4 (t), 25.8 (t), 22.9 (t), 14.2 (q).

The compounds (16-21, 23-28, 30-31, 33-34) were synthesized by usingvarious carboxylic acids or combining a variety of Wittig's salts byapplying the method for synthesizing the compound 22 (reaction route D).Synthetic examples of these compounds are herein illustrated.

Compound 16

The aldehyde D1 was reacted with tridecanetriphenyl-phosphonium bromidein place of the Wittig's salt in the synthesis of the compound 22.Synthesis was further conducted by applying the route D. The amineobtained by reducing an azide group was reacted with tetracosanoic acidin place of (R)-2-acetoxytetracosanoic acid D8, and the syntheticprocess was followed by applying the route D to obtain the compound 16.Data! α!²⁴ _(D) =+28.2° (pyridine, c=0.27) MS: FDMS 831. IR: (cm⁻¹, KBr)3350, 2920, 2850, 1640, 154G, 1465. mp: 146°-147° C. NMR: ¹ H (500 MHz,C₅ D₅ N; 27° C.)

δ (ppm) 8.45 (1H, d, J=8.5 Hz), 5.55 (1H, d, J=3.7 Hz), 5.24 (1H, m),4.64 (2H, m), 4.52 (1H, m), 4.48 (1H, m), 4.38 (4H, m), 4.28 (2H, bs),2.41 (2H, t, J=6.3.Hz), 2.24 (1H, m), 1.88 (2H, m), 1.78 (2H, m), 1.64(1H, m), 1.10-1.45 (62H, m), 0.85 (6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅D₅ N; 27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 71.6 (d),71.0 (d), 70.3 (d), 68.7 (t), 62.7 (t), 51.5 (d), 36.8 (t), 34.3 (t),32.1 (t), 30.4 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.9 (t), 29.8 (t),29.7 (t), 29.6 (t), 26.5 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 17

The amine obtained by reducing an azide group by applying the route D inthe synthesis of the compound 22 was reacted with tetracosanoic acid inplace of (R)-2-acetoxytetracosanoic acid D8, and the synthetic processwas followed by applying the route D to obtain the compound 17. Data!α!²³ _(D) =+42.40 (pyridine, c=0.8) MS: FDMS 817. IR: (cm⁻¹, KBr) 3400,2950, 2870, 1645, 1535, 1475, 1080. mp: 166°-168° C. NMR: ¹ H (500 MHz,C₅ D₅ N; 27° C.)

δ (ppm) 8.43 (1H, d, J=8.6 Hz), 5.55 (1H, d, J=3.7 Hz), 5.23 (1H, m),4.64 (1H, dd, J=5.5, 10.4 Hz), 4.62 (1H, dd, J=4.3, 10.4 Hz), 4.52 (1H,m), 4.49 (1H, bt, J=6.1 Hz), 4.33-4.42 (4H, m), 4.30 (2H, m), 2.42 (2H,dd, J=6.7, 7.3 Hz), 2.26 (1H, m), 1.86 (2H, m), 1.78 (2H, m), 1.65 (1H,m), 1.16-1.46 (60H, m), 0.85 (6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N;27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.4 (d), 71.5 (d),70.9 (d), 70.2 (d), 68.6 (t), 62.6 (t), 51.4 (d), 36.7 (t), 34.3 (t),32.1 (t), 30.3 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.8 (t), 29.8 (t),29.7 (t), 29.7 (t), 29.5 (t), 26.4 (t), 26.3 (t), 22.9 (t), 14.2 (q).

Compound 18

The aldehyde D1 was reacted with decanetriphenyl-phosphonium bromide inplace of the Wittig's salt D2 in the synthesis of the compound 22. Thesubsequent synthetic process was followed by applying the route D. Theamine obtained by reducing the azide group was reacted withtetracosanoic acid in place of (R)-2-acetoxytetracosanoic acid D8, andthe subsequent steps were followed by applying the route D to obtain thecompound 18. Data! α!²⁴ _(D) =+30.00 (pyridine, c=0.2) MS: FDMS 789. IR:(cm⁻¹, KBr) 3350, 2920, 2840, 1640, 1540, 1465. mp: 154°-155° C. NMR: ¹H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.45 (1H, d, J=8.5 Hz), 5.55 (1H, d, J=3.7 Hz), 5.24 (1H, m),4.64 (2H, m), 4.53 (1H, m), 4.49 (1H, m), 4.39 (4H, m), 4.30 (2H, bs),2.42 (2H, t, J=6.7 Hz), 2.25 (1H, m), 1.88 (2H, m), 1.78 (2H, m), 1.64(1H, m), 1.15-1.45 (56H, m), 0.85 & 0.84 (each 3H, t, J=7.3 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.3 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 71.6 (d),71.0 (d), 70.3 (d), 68.7 (t), 62.7 (t), 51.5 (d), 36.8 (t), 34.3 (t),32.1 (t), 30.3 (t), 29.6-30.1, 26.5 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 19

The aldehyde D1 was reacted with hexanetriphenyl-phosphonium bromide inplace of the Wittig's salt D2 in the synthesis of the compound 22. Thesubsequent synthetic process was followed by applying the route D. Theamine obtained by reducing the azide group was reacted withtetracosanoic acid in place of (R)-2-acetoxytetracosanoic acid D8, andthe subsequent steps were followed by applying the route D to obtain thecompound 19. Data! MS: FDMS 732. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.45 (1H, d, J=8.6 Hz), 6.97 (1H, bs), 6.62 (1H, bs), 6.52 (1H,m), 6.43 (1H, bs), 6.29 (1H, d, J=3.7 Hz), 6.06 (1H, bs), 5.58 (1H, d,J=3.7 Hz), 5.26 (1H, m), 4.66-4.68 (2H, m), 4.55 (1H, bs), 4.51 (1H, m),4.38-4.42 (4H, m), 4.30 (1H, bs), 2.44 (2H, t, J=7.3 Hz), 1.80-1.88 (4H,m), 1.19-1.59 (50H, m), 0.88 & 0.81 (each 3H, t, J=6.7 Hz).

Compound 20

Synthesis was conducted by applying the route D in the synthesis of thecompound 22. The amine obtained by reducing the azide group was reactedwith hexacosanoic acid in place of (R)-2-acetoxytetracosanoic acid D8,and the subsequent steps were followed by applying the route D to obtainthe compound 20. Data! α!²⁵ _(D) =+37.70 (pyridine, c=0.97) MS: FDMS845. IR: (cm⁻¹, KBr) 3380, 2920, 2840, 1635, 1545, 1465, 1065. mp:156°-158° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.46 (1H, d, J=8.6 Hz), 6.42 (1H, m), 6.09 (1H, m), 5.57 (1H, d,J=3.7 Hz), 5.26 (1H, m), 4.66 (2H, m), 4.55 (1H, m), 4.51 (1H, t, J=5.8Hz), 4.41 (4H, m), 4.32 (2H, m), 2.44 (2H, t, J=7.0 Hz), 2.28 (1H, m),1.90 (2H, m), 1.81 (2H, m), 1.68 (1H, m), 1.15-1.45 (64H, m), 0.88 (6H,t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 71.6 (d),71.0 (d), 70.3 (d), 68.7 (t), 62.7 (t), 51.5 (d), 36.8 (t), 34.4 (t),32.1 (t), 30.4 (t), 30.1 (t), 30.03 (t), 29.99 (t), 29.93 (t), 29.87(t), 29.81 (t), 29.76 (t), 29.6 (t), 26.5 (t), 26.4 (t), 22.9 (t), 14.3(q).

Compound 33

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, tridecane-triphenylphosphonium bromide,and the amine synthesized in accordance with the route D, with an azidegroup reduced was treated with, instead of the (R)-2-acetoxytetracosanicacid D8, hexacosanic acid. After this, the synthesis was continued inaccordance with the route D to give Compound 33. Data! α!²³ _(D) =+43.90(pyridine, c=0.81) MS: negative FAB-MS 857 (M-H)⁻ ! IR: (cm⁻¹, KBr)3300, 2980, 2850, 1640, 1540, 1470, 1070. mp: 130°-135° C. NMR: ¹ H (500MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.47 (1H, d, J=8.5 Hz), 6.97 (1H, d, J=1.8Hz), 6.63 (1H, bs),6.54 (1H, m), 6.44 (1H, d, J=5.5 Hz), 6.32 (1H, bs), 6.09 (1H, d, J=5.0Hz), 5.58 (1H, d, J=3.7 Hz), 5.27 (1H, m), 4.65-4.70 (2H, m), 4.56 (1H,bs), 4.52 (1H, t, J=5.5 Hz), 4.37-4.47 (4H, m), 4.31-4.35 (2H, m), 2.45(2H, t, J=7.3 Hz), 1.78-1.97 (4H, m), 1.26-1.69 (68H, m), 0.88 (6H, t,J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 71.6 (d),71.0 (d), 70.3 (d), 68.7 (t), 62.7 (t), 51.4 (d), 36.8 (t), 34.4 (t),32.1 (t), 30.4 (t), 10 30.2 (t), 30.0 (t), 30.0 (t) 29.9 (t), 29.9 (t),29.8 (t), 29.6 (t), 26.5 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 34

In the synthesis of Compound 22, the amine synthesized in accordancewith the route D, with an azide group remained was treated with, insteadof the (R)-2-acetoxytetracosanic acid D8, octacosanic acid. After this,the synthesis was continued in accordance with the route D to giveCompound 34. Data! α!²⁴ _(D) =+46.80° (pyridine, c=0.47) MS: negativeFAB-MS 871 (M-H)⁻ !. IR: (cm⁻¹, KBr) 3350, 2930, 2850, 1640, 1540, 1470,1080. mp: 142°-145° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.46 (1H, d, J=7.9 Hz), 6.92-6.98 (1H, m), 6.59-6.63 (1H, m),6.53 (1H, bs), 6.44 (1H, d, J=5.5 Hz), 6.33 30 (1H, bs), 6.07 (1H, d,J=5.5 Hz), 5.58 (1H, d, J=3.7 Hz), 5.25-5.30(1H, m), 4.62-4.70 (2H, m),4.56 (1H, bs), 4.52 (1H, t, J=6.1 Hz), 4.36-4.47 (3H, m), 4.29-4.35 (2H,m), 2.44 (2H, t, J=6.7 Hz), 1.78-1.97 (4H, m), 1.25-1.72 (70H, m), 0.88(6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 71.6 (d),71.0 (d), 70.3 (d), 68.6 (t), 62.6 (t), 51.4 (d), 36.8 (t), 34.3 (t),32.1 (t), 30.3 (t), 30.1 (t), 30.0 (t), 30.0 (t), 29.9 (t), 29.9 (t),29.8 (t), 29.7 (t), 29.6 (t), 26.5 (t), 26.4 (t), 22.9 (t), 14.3 (q).

Compound 21

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, tridecane-triphenylphosphonium bromide.After this, the synthesis was continued in accordance with the route Dto give Compound 21. Data! MS: FDMS 847. IR: (cm⁻¹, KBr) 3400, 2950,2870, 1645, 1535, 1475, 1080. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.50 (1H, d, J=9.2 Hz), 5.59(1H, d, J=3.7 Hz), 5.27 (1H, m),4.64 (2H, m), 4.58 (1H, m), 4.53 (1H, m), 4.48 (2H, m), 4.30-4.42 (4H,m), 4.27 (1H, m), 2.29 (1H, m), 2.18 (1H, m), 1.98 (1H, m), 1.87 (2H,m), 1.74 (1H, m), 1.67 (2H, m), 1.15-1.46 (60H, m), 0.84 (6H, t, J=6.7Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 174.9 (s), 101.2 (d), 76.5 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.4 (d), 35.5 (t),34.4 (t), 32.1 (t), 30.3 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.5 (t),26.4 (t), 25.8 (t), 22.9 (t), 14.2 (q).

Compound 23

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, decanetriphenyl-phosphonium bromide.After this, the synthesis was continued in accordance with the route Dto give Compound 23. Data! α!²⁴ _(D) =+59.20 (pyridine, c=0.1) MS: FDMS805. IR: (cm⁻¹, KBr) 3400, 2950, 2870, 1645, 1535, 1475, 1080. mp:193°-194° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.50 (1H, d, J=9.2 Hz), 5.59 (1H, d, J=3.7 Hz), 5.28 (1H, m),4.64 (2H, m), 4.58 (1H, m), 4.53 (1H, m), 4.48 (2H, m), 4.30-4.42 (4H,m), 4.27 (1H, m), 2.29 (1H, m), 2.18 (1H, m), 1.98 (1H, m), 1.87 (2H,m), 1.74 (1H, m), 1.66 (2H, m), 1.15-1.46 (54H, m), 0.84 (6H, t, J=6.7Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 174.9 (s), 101.2 (d), 76.5 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.4 (d), 35.5 (t),34.4 (t), 32.1 (t), 30.3 (t), 30.1 (t), 30.0 (t), 29.9 (t), 29.5 (t),26.4 (t), 25.8 (t), 22.9 (t), 14.2 (q).

Compound 24

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, hexanetriphenyl-phosphonium bromide.After this, the synthesis was continued in accordance with the route Dto give Compound 24. Data! α!²³ _(D) =+67.1° (pyridine, c=1.32) MS: FDMS749. IR: (cm⁻¹, KBr) 3300, 2870, 2800, 1630, 1605, 1515, 1455, 1060. mp:145°-147° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.) δ (ppm) 8.50 (1H, d,J=9.2 Hz), 6.70 (2H, bd, J=6.1 Hz), 6.53 (1H, bs), 6.31 (1H, bs), 6.08(1H, bs), 5.61 (1H, d, J=3.7 Hz), 5.29 (1H, m), 4.64-4.67 (2H, m), 4.59(1H, m), 4.54 (1H, m), 4.47-4.51 (2H, m), 4.32-4.43 (4H, m), 4.26 (1H,m), 1.64-2.27 (4H, m), 1.20-1.40 (50H, m), 0.87 & 0.82 (each 3H, t,J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.5 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.4 (d), 35.5 (t),34.4 (t), 32.0 (t), 30.2 (t), 29.9 (t), 29.8 (t), 29.7 (t), 29.5 (t),26.3 (t), 25.8 (t), 22.9 (t), 22.8 (t), 14.21 (q), 14.18 (q).

Compound 25

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, tridecane-triphenylphosphonium bromide,and the amine synthesized in accordance with the route D, with an azidegroup reduced was treated with, instead of the (R)-2-acetoxytetracosanicacid D8, (R)-2-acetoxyhexacosanic acid. After this, the synthesis wascontinued in accordance with the route D to give Compound 25. Data! α!²³_(D) =+45.20 (pyridine, c=1.0) MS: FDMS 875. IR: (cm⁻¹, KBr) 3400, 2950,2870, 1645, 1535, 1475, 1080. mp: 198°-199° C. NMR: ¹ H (500 MHz, C₅ D₅N; 27° C.)

δ (ppm) 8.49 (1H, d, J=9.2 Hz), 7.53 (1H, bs), 7.02 (1H, bs), 6.70 (1H,d, J=6.1 Hz), 6.65 (1H, bs), 6.53 (1H, bs), 6.30 (1H, bs), 6.08 (1H, d,J=5.5 Hz), 5.57 (1H, d, J=3.7 Hz), 5.26 (1H, m), 4.62 (2H, dd, J=4.9,10.4 Hz), 4.58 (1H, m), 4.51 (1H, bs), 4.46 (2H, m), 4.28-4.41 (4H, m),4.26 (1H, m), 2.27 (1H, m), 2.17 (1H, m), 1.98 (1H, m), 1.87 (2H, m),1.74 (1H, m), 1.66 (2H, m), 1.16-1.46 (64H, m), 0.85 (6H, t, J=6.1 Hz).¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.5 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.2 (t), 62.6 (t), 50.5 (d), 35.5 (t),34.4 (t), 32.1 (t), 30.3 (t), 30.1 (t), 29.9 (t), 29.9 (t), 29.6 (t),26.4 (t), 25.8 (t), 22.9 (t), 14.2 (q).

Compound 26

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, tetradecane-triphenylphosphonium bromide,and the amine synthesized in accordance with the route D, with an azidegroup reduced was treated with, instead of the (R)-2-acetoxytetracosanicacid D8, (R)-2-acetoxyhexacosanic acid. After this, the synthesis wascontinued in accordance with the route D to give Compound 26. Data! α!²³_(D) =+46.50 (pyridine, c=0.7) MS: FDMS 889. IR: (cm⁻¹, KBr) 3400, 2950,2870, 1645, 1535, 1475, 1080. mp: 205°-206° C. NMR: ¹ H (500 MHz, C₅ D₅N; 27° C.)

δ (ppm) 8.50 (1H, d, J=9.2 Hz), 7.56 (1H, bs), 7.04 (1H, bs), 6.71 (1H,d, J=6.7 Hz), 6.66 (1H, bs), 6.54 (1H, bs), 6.32 (1H, bs), 6.10 (1H, d,J=5.5 Hz), 5.58 (1H, d, J=3.7 Hz), 5.27 (1H, m), 4.63 (2H, m), 4.58 (1H,m), 4.52 (1H, bs), 4.47 (2H, m), 4.28-4.41 (4H, m), 4.27 (1H, m), 2.27(1H, m), 2.18 (1H, m), 1.99 (1H, m), 1.88 (2H, m), 1.74 (1H, m), 1.66(2H, m), 1.16-1.46 (66H, m), 0.85 (6H, t, J=6.7 Hz). ¹³ C (125 MHz, C₅D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.5 (d), 73.0 (d)r 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.4 (d), 35.5 (t),34.4 (t), 32.1 (t), 30.3 (t), 30.1 (t), 29.9 (t), 29.9 (t), 29.5 (t),26.4 (t), 25.8 (t), 22.9 (t), 14.2 (q).

Compound 27

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, heptadecane-triphenylphosphonium bromide,and the amine synthesized in accordance with the route D, with an azidegroup reduced was treated with, instead of the (R)-2-acetoxytetracosanicacid D8, (R)-2-acetoxyhexacosanic acid. After this, the synthesis wascontinued in accordance with the route D to give Compound 27. Data! α!²³_(D) =+46.00 (pyridine, c=0.8) MS: FDMS 903. IR: (cm⁻¹, KBr) 3400, 2950,2870, 1645, 1535, 1475, 1080. mp: 200°-201° C. NMR: ¹ H (500 MHz, C₅ D₅N; 27° C.)

δ (ppm) 8.49 (1H, d, J=9.2 Hz), 7.54 (1H, bs), 7.02 (1H, bs), 6.69 (1H,d, J=6.7 Hz), 6.66 (1H, bs), 6.53 (1H, bs), 6.30 (1H, bs), 6.08 (1H, d,J=4.9 Hz), 5.57 (1H, d, J=3.7 Hz), 5.25 (1H, m), 4.62 (2H, dd, J=4.9,10.4 Hz), 4.57 (1H, m), 4.51 (1H, bs), 4.46 (2H, m), 4.28-4.40 (4H, m),4.26 (IH, m), 2.26 (1H, m), 2.17 (1H, m), 1.98 (1H, m), 1.87 (2H, m),1.73 (1H, m), 1.65 (2H, m), 1.16-1.46 (68H, m), 0.86 (6H, t, J=6.7 Hz).¹³ C-(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.4 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.5 (d), 70.9 (d), 70.1 (d), 68.1 (t), 62.6 (t), 50.5 (d), 35.5 (t),34.3 (t), 32.1 (t), 30.3 (t), 30.1 (t), 29.9 (t), 29.6 (t), 26.4 (t),25.8 (t), 22.9 (t), 14.2 (q).

In another method for synthesizing Compounds 25, 26 and 27, Cereblin Ewas used. In the synthesis of Compound 22, Cereblin E (a product ofAlfred Baker Chemicals or K & K Laboratories, Inc.), a tetraol, was usedinstead of the triol D10, and a mixture of Compounds 25, 26 and 27 wasobtained in accordance with the route D. This mixture was subjected to ahigh performance liquid chromatography ("D-ODS-5" manufactured by YMCCo., Ltd., solvent: 100% methanol, 45° C.) for separation. Thus, eachcompound was obtained.

Compound 28

In the synthesis of Compound 22, the amine 15 synthesized in accordancewith the route D, with an azide group reduced was treated with, insteadof the (R)-2-acetoxytetracosanic acid D8, (S)-2-acetoxytetracosanicacid. After this, the synthesis was continued in accordance with theroute D to give Compound 28. Data! α!²³ _(D) =+36.8° (pyridine, c=2.0)MS: FDMS 833.

IR: (cm⁻¹, KBr) 3400, 2950, 2870, 1645, 1535, 1475, 1080. mp: 174°-176°C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.55 (1H, d, J=8.5 Hz), 5.61 (1H, d, J=4.3 Hz), 5.26 (1H, m),4.68 (1H, dd, J=5.5, 10.4 Hz), 4.63 (1H, 30 dd, J=3.7, 9.8 Hz), 4.56(2H, bs), 4.49 (1H, t, J=5.5 Hz), 4.46 (1H, dd, J=3.7, 9.8 Hz), 4.38(2H, m), 4.34 (1H, dd, J=4.3, 11.0 Hz), 4.31 (1H, bd, J=8.6 Hz), 4.20(1H, dd, J=3.7, 7.9 Hz), 2.26 (1H, m), 2.19 (1H, m), 1.99 (1H, m), 1.84(2H, m), 1.74 (1H, m), 1.58-1.70,(2H, m), 1.16-1.46 (58H, m), 0.85 (6H,t, J=6.7 Hz). ¹³ C (125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.2 (d), 76.7 (d), 73.0 (d), 72.5 (d), 72.4 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.0 (t), 62.6 (t), 50.5 (d), 35.6 (t),34.6 (t), 32.1 (t), 30.3 (t), 30.1 (t), 29.9 (t), 29.9 (t), 29.6 (t),26.3.(t), 25.8 (t), 22.9 (t), 14.2 (q).

Compound 30

In the synthesis of Compound 22, the aldehyde D1 was treated with,instead of the Wittig salt D2, 11-methyl-9-dodecentriphenylphosphoniumbromide, and the amine synthesized in accordance with the route D, withan azide group reduced was treated with, instead of the(R)-2-acetoxytetracosanic acid D8, (S)-2-acetoxytetracosanic acid. Afterthis, the synthesis was continued in accordance with the route D to giveCompound 30. Data! α!²⁵ _(D) =+46.20 (pyridine, c=1.0) MS: FDMS 847. IR:(cm⁻¹, KBr) 3400, 3250, 2870, 2810, 1640, 1525, 1455, 1355, 1320, 1275,1145, 1060. mp: 169.0°-171.0° C. NMR: ¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 8.57 (1H, d, J=9.2 Hz), 6.64 (2H, m), 6.45 (1H, m), 6.30 (1H,m), 6.11 (2H, m), 5.65 (1H, d, J=3.7 Hz), 5.29 (2H, m), 4.65-4.75 (2H,m), 4.59 (2H, m), 4.51 (2H, m), 4.30-4.45 (4H, m), 4.22 (1H, m), 2.30(1H, m), 2.21 (1H, m), 2.02 (1H, m), 1.6-2.0 (5H, m), 1.49 (1H, m),1.15-1.35 (56H, m), 0.89 (3H, t, J=6.1 Hz), 0.87 (6H, d, J=6.1 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 175.0 (s), 101.3 (d), 76.7 (d), 73.0 (d), 72.4 (d), 72.3 (d),71.6 (d), 70.9 (d), 70.1 (d), 68.0 (t), 62.6 (t), 50.6 (d), 39.2 (t),35.6 (t), 34.6 (t), 32.1 (t), 30.3 (t), 30.2 (t), 30.1 (t), 30.0 (t),29.9 (t), 29.6 (t), 28.1 (d), 27.7 (t), 26.3 (t), 25.8 (t), 22.9 (t),22.7 (q), 14.2 (q).

Compound 31

In the synthesis of Compound 22, the aldehyde D1 was 5 treated with,instead of the Wittig salt D2, 11-methyl-9-dodecentriphenylphosphoniumbromide, and the amine synthesized in accordance with the route D, withan azide group reduced was treated with, instead of the(R)-2-acetoxytetracosanic acid D8, tetracosanic acid. After this, thesynthesis was continued in accordance with the route D to give Compound31. Data! α!²⁵ _(D) =+43.6° (pyridine, c=0.44) MS: FDMS 831. IR: (cm⁻¹,KBr) 3300, 2880, 2810, 1630, 1535, 1455, 1055. mp: 197.0°-198.5° C. NMR:¹ H (500 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 20 8.44 (1H, d, J=8.6 Hz), 5.57 (1H, d, J=3.7 Hz), 5.25 (1H, m),4.63-4.70 (2H, m), 4.54 (1H, d, J=3.1 Hz), 4.50 (1H, t, J=6.1 Hz),4.35-4.45 (4H, m), 4.31 (2H, m), 2.44 (2H, t, J=7.3 Hz), 2.28 (1H, m),1.90 (2H, m), 1.81 (2H, m), 1.68 (1H, m), 1.49 (1H, m), 1.2-1.45 (56H,m), 1.15 (2H, m), 0.88 (3H, t, J=6.7 Hz), 0.87 (6H, d, J=6.7 Hz). ¹³ C(125 MHz, C₅ D₅ N; 27° C.)

δ (ppm) 173.2 (s), 101.5 (d), 76.7 (d), 73.0 (d), 72.5 (d), 30 71.6 (d),71.0 (d), 70.3 (d), 68.7 (t), 62.7 (t), 51.4 (d), 39.3 (t), 36.8 (t),34.4 *(t), 32.1 (t), 30.4 (t), 30.23 (t), 30.15 (t), 30.03 (t), 30.00(t), 29.91 (t), 29.87 (t), 29.81 (t), 29.75 (t), 29.6 (d), 28.2 (d),27.7 (t), 26.5 (t), 26.4 (t), 22.9 (t), 22.8 (q), 14.3 (q).

EXAMPLES

The following are experimental examples of the present invention.However, the present invention is not limited by the following examples.

Pharmacological Test 1: Proliferation-Stimulating Effect on Marrow Cellof Mouse

Marrow cells were prepared from the thigh bone of a 7 week old femaleBALB/c mouse purchased from Japan SLC Co., Ltd., and a mononuclear cellfraction (MNF) obtained by fractionation using a lympholyte-M (CedarLane, Ontario, Canada). was used in the following experiment.

The concentration of the MNF was adjusted to 1.5×10⁶ cells/ml by using10% FCS RPMI 1640 (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan) as aculture medium. 10 μl/well of a sample with a predeterminedconcentration and 100 μl/well of the above-prepared MNF were placed on around-bottomed 96 well plate, and incubated under the conditions of 37°C. and 5% CO₂ for 72 hours. Thereafter, 0.5 μCi/well of ³ H-thymidine (³H-TdR) was added. After 8 hour incubation, the cells were harvested, andthe amount of the 3H-TdR taken in the nuclei was measured by a liquidscintillation counter.

The percentages of the values of experimental plot to the value ofcontrol are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Sample/Concentration                                                                         Uptake of .sup.3 H-TdR (%)                                     (μg/ml)     10.sup.0                                                                             10.sup.-1 10.sup.-2                                                                          10.sup.-3                                ______________________________________                                         1             1348   465       263  134                                       5             1143   377       261  234                                       8             1056   232        81  129                                       7              972   631       351  313                                      32              871   405       151  115                                      29              865   382       187   97                                      14             1184   511       132  134                                      17             1140   462       149  159                                      18             1157   472       124  129                                      16             1244   495       152  115                                      19             1326   499       207  173                                       9             1236   547       103  134                                       4             1332   297        75  151                                      15              979   292       101   69                                       6             1639   391       196   71                                      20              982   466       201   67                                       2              915   295        92  123                                       3             1098   234        87   84                                      10             1036   356        90   77                                      31              624   326       104  101                                      24              576   197        79   77                                      23              761   312        89   81                                      30              712   293       105   92                                      21              799   244        96   84                                      22              613   226       116  104                                      28             1051   192       170  130                                      25             1370   331       161  153                                      26             1564   271       183  156                                      27             1091   220       165  156                                      33             1253   460       330  175                                      34             1085   272       183  150                                      ______________________________________                                    

As shown in Table 1, all of the samples showed a remarkablemarrow-cell-proliferation-accelerating effect.

Pharmacological Test 2: Effect on Marrow Cell of Monkey

Marrow cells were prepared from the humerus of a croo monkey, and an MNFobtained by fractionation using a Lymphoprep (Nycomed Pharma AS, Oslo,Norway) was used in the following experiment.

The MNF was suspended in an RPMI 1640 medium added with 10% blood plasmaof a croo monkey to make its concentration 1×10⁶ cells/ml.

10 μl/well of a sample with a predetermined concentration and 100μl/well of the above-prepared MNF were placed on a round-bottomed 96well plate, and incubated under the conditions of 37° C. and 5% CO₂ for4 days. Thereafter, 0.5 μCi/well of ³ H-TdR was added. After 6 hours,the cells were harvested, and the amount of the ³ H-TdR taken in thenuclei was measured by a liquid scintillation counter. The percentagesof the values of experimental plot to the value of control are shown inTable 2.

                  TABLE 2                                                         ______________________________________                                        Sample/Concentration                                                                              Uptake of .sup.3 H-TdR (%)                                μg/ml            10.sup.-1                                                                            10.sup.-2                                          ______________________________________                                        25                  184    186                                                33                  177    194                                                ______________________________________                                    

As shown in Table 2, both of the samples showed a remarkable3H-TdR-uptake-accelerating effect.

Pharmacological Test 3: Proliferation-Stimulating Effect on MononuclearCell Fraction of Human Umbilical Cord Blood

It is extremely difficult to obtain human marrow cells. In addition,human umbilical cord blood contains stem cells (Nakahata, T. & Ogwa, M.,J. Clin. Inveet. 70, 1324-1328 (1982)), so that it can be a good sourceof hematopoietic stem/progenitor cell supply (H. E. Broxneyer et al,Proc. Natl. Acad. Sci. USA, 86, 3828-3832 (1989)). For these reasons,the effect on human was examined by using, instead of human marrowcells, human umbilical cord blood.

To human umbilical cord blood was. added an equal amount of RPMI 1640.This was placed-on a Lymphoprep and centrifuged. The mononuclear cellfraction (MNF) thus obtained was used in the following experiment.

The concentration of the MNF was adjusted to 1×10⁶ cells/ml by using anRPMI 1640 added with 10% auto-blood plasma as a culture medium. 10μl/well of a sample with a predetermined concentration and 100 μl/wellof the above-prepared MNF were placed on a round-bottomed 96 well plateand incubated under the conditions of 37° C. and 5% CO₂ for 4 days.Thereafter, 0.5 μCi/well of ³ H-TdR was added. After 8 hour incubation,the cells were harvested, and the amount of the 3H-TdR taken in thenuclei was measured by a liquid scintillation counter.

The percentages of the values of experimental plot to the value ofcontrol are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Sample/Concentration                                                                        Uptake of .sup.3 H-TdR (%)                                      (μg/ml)    10.sup.-1   10.sup.-2                                                                            10.sup.-3                                    ______________________________________                                        27            450         486    344                                          23            402         344    197                                          21            552         530    305                                          20            692         474    507                                          22            362         357    204                                          28            356         331    182                                          14            233         141     96                                          18            298         177    135                                          16            311         204    216                                          17            318         233     98                                          25            336         319    229                                          33            409         256    228                                          34            467         258    291                                          ______________________________________                                    

The data was divided by a horizontal line with every series ofexperiments..

As shown in Table 3, all of the samples showed a remarkable3H-TdR-uptake-accelerating effect.

From the above results, it was clearly proved that the compoundsrepresented by the formula (A) have a stimulating effect onproliferation of the marrow cells or umbilical cord blood cells ofmouse, monkey and human.

Pharmacological Test 4: Life-Span-Increasing Effect on Irradiation of aLethal Dose of Radiation

An experiment was carried out by using 6 week old female BDF1 micepurchased from Japan SLC Co., Ltd., with 10 mice made one group. Theentire bodies of the mice were iradiated with 9 GY of X-rays by using aHitachi X-ray irradiator (MBR-1520R), and the day on which the X-ray wasirradiated was referred to as "day 0". On days 0, 4 and 8, each samplewas administered to the caudal vein of the mice at a dose of 0.1 mg/kg,and the mice were observed with respect to their life or death for 40days.

The numbers of surviving mice on days 10, 15, 20, 25, 30, 35 and 40 areshown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Radiation-Protecting Effect                                                          Number of Surviving Mice                                               Compound No.                                                                           10     15    20    25   30    35   40 (days)                         ______________________________________                                        Control  10      8    4     3    1     0    0                                  5       10      9    9     9    9     9    9                                 Control  10      9    5     3    1     0    0                                  1       10     10    10    9    9     9    9                                  6        9      6    2     2    2     2    2                                  7       10      8    6     5    5     5    5                                 10       10      8    7     7    7     7    7                                 Control  10      5    1     0    0     0    0                                 14       10     10    10    9    9     9    9                                 18       10     10    8     7    7     7    7                                 19       10     10    10    10   10    10   10                                 9       10      8    6     6    6     6    6                                  4       10     10    8     7    5     5    5                                  8       10      5    1     1    1     1    1                                  2       10     10    9     9    9     9    8                                  3       10      9    8     8    8     8    8                                 32       10      9    4     3    3     3    3                                 Control  10      5    2     0    0     0    0                                 24       10      9    9     9    9     9    9                                 23       10     10    9     9    9     9    9                                 21       10     10    10    10   10    10   10                                22       10     10    10    9    8     8    8                                 17       10     10    9     9    9     9    9                                 16       10      6    6     6    6     6    6                                 15       10      9    6     6    6     6    6                                 20       10      8    7     7    6     6    6                                 25       10     10    7     7    5     5    5                                 Control  10      7    3     2    0     0    0                                 31       10     10    9     9    9     9    9                                 30       10     10    10    10   10    10   10                                28       10     10    10    8    8     8    8                                 26       10      9    9     8    8     8    8                                 27       10     10    9     9    9     9    9                                 29       10      9    8     8    8     8    8                                 Control   8      1    0     0    0     0    0                                 33       10      8    7     5    5     5    5                                 34       10     10    10    9    9     9    9                                 ______________________________________                                    

Pharmacological Test 5: Thrombocytopenia-Inhibiting Effect

The thrombocytopenia-inhibiting effect of each sample upon anX-ray-irradiated mouse, which is one of models with a decreased numberof blood platelets, was examined.

An experiment was carried out by using 6 week old female BDF₁ micepurchased from Japan SLC Co., Ltd., with 6 mice made one group.

5 Gy of X ray was irradiated to the entire body of the mice by a HitachiX-ray irradiator CMBR-1520R). Within 2 hours after the irradiation, eachsample was administered to the caudal vein of the mice at an amount of0.1 mg/kg.

After 10 days, blood was collected from the fundus vein of the mice, andthe number of blood platelets was measured by a sequential multi-channelhemocytometer E-2500/cs (Toa Iyo Denshi Kabushiki Kaisha). The number ofblood platelets of the non-treated group, that of themedium-administered group, and that of the sample-administered group areshown in Table 5.

                  TABLE 5                                                         ______________________________________                                                    Number of Blood Platelets                                                     (× 10.sup.4 /μl)                                         Compound No.                                                                              Mean value ± Standard deviation                                ______________________________________                                        Non-treatment                                                                             68.2 ± 6.5                                                     Vehicle     10.3 ± 4.1                                                     31          27.7 ± 5.4                                                     14          22.3 ± 6.6                                                     24          21.6 ± 7.2                                                     23          21.0 ± 5.9                                                     30          22.5 ± 3.5                                                     21          22.7 ± 3.7                                                      1          25.4 ± 6.8                                                     25          15.6 ± 5.3                                                     34          24.4 ± 5.6                                                     33          23.9 ± 6.5                                                     Non-treatment                                                                              96.9 ± 11.6                                                   Vehicle      6.8 ± 2.5                                                     22          25.4 ± 5.1                                                     28          20.4 ± 4.5                                                      5          20.3 ± 4.5                                                     18          24.3 ± 8.6                                                     16          21.1 ± 6.2                                                     19          23.4 ± 4.2                                                      9          17.6 ± 3.4                                                      4          14.3 ± 4.7                                                     15          17.8 ± 2.4                                                      6          15.4 ± 3.2                                                     Non-treatment                                                                             73.0 ± 2.0                                                     Vehicle      6.7 ± 1.2                                                     17          18.5 ± 4.4                                                     20          19.8 ± 7.3                                                      8           8.1 ± 2.6                                                      2          21.5 ± 5.4                                                      3          20.6 ± 4.5                                                      7          12.3 ± 4.0                                                     26          19.8 ± 4.3                                                     27          16.0 ± 4.1                                                     10          19.6 ± 4.0                                                     32          16.4 ± 3.2                                                     29          18.1 ± 5.0                                                     ______________________________________                                    

As shown in Table 5, all of the samples showed a remarkableblood-platelet-decrease-inhibitory effect.

From the above results, it was clearly proved that the compoundsrepresented by the formula (A) have a remarkableblood-platelet-decrease-inhibitory effect upon irradiation of radiation.

Subsequently, the effect on blood platelet was examined using normalmice.

Pharmacological Test 6: Blood-Platelet-Increasing Effect upon Mouse

An experiment was carried out by using 6 week old female BDF₁ micepurchased from Japan SLC Co., Ltd., with 5 mice made one group.

Each sample was administered to the caudal vein of the mice at a dose of0.1 mg/kg. After 6 days, blood was collected from the fundus vein of themice, and the number of blood platelets was measured by a sequentialmulti-channel hemocytometer E-2500/cs (Toa Iyo Denshi Kabushiki Kaisha).The number of blood platelets of the vehicle-administered group, andthat of the sample-administered group are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                    Number of Blood Platelets                                                     (× 10.sup.4 /μl)                                         Compound No.                                                                              Mean value ± Standard deviation                                ______________________________________                                        Vehicle     58.2 ±     7.1                                                 31          108.0 ±    7.0                                                 14          101.6 ±    8.3                                                 24          102.6 ±    9.9                                                 23          108.7 ±    14.8                                                30          106.2 ±    9.0                                                 21          94.8 ±     7.7                                                  1          112.2 ±    6.5                                                 34          110.1 ±    9.0                                                 22          104.1 ±    7.7                                                 28          103.6 ±    8.8                                                 17          92.1 ±     11.3                                                18          111.7 ±    5.4                                                 16          114.7 ±    13.0                                                19          106.4 ±    12.7                                                Vehicle     63.0 ±     7.0                                                  9          100.5 ±    8.3                                                  4          83.1 ±     6.5                                                 15          84.7 ±     6.0                                                  6          93.0 ±     12.1                                                20          110.9 ±    10.6                                                 8          96.6 ±     3.2                                                  2          96.3 ±     7.3                                                  3          102.0 ±    10.8                                                 7          76.0 ±     5.1                                                 26          113.7 ±    7.1                                                 27          101.3 ±    7.1                                                 10          87.2 ±     4.0                                                 32          88.3 ±     4.2                                                 29          86.3 ±     3.1                                                 Vehicle     71.1 ±     4.4                                                  5          106.0 ±    9.0                                                 25          124.1 ±    14.7                                                33          142.3 ±    10.2                                                ______________________________________                                    

As shown in Table 6, all of the samples clearly showed ablood-platelet-increasing effect.

As shown in Table 6, it was clearly proved that the compoundsrepresented by the formula (A) have a remarkableblood-platelet-increasing effect upon a normal mouse.

Subsequently, in order to examine the effect on Primates, the effect ofCompound 33 was examined as a representative of the compoundsrepresented by the formula (A), by using normal croo monkeys.

Pharmacological Test 7: Blood-Platelet-Increasing Effect upon Monkey

Six croo monkeys (female, 3 to 5 years old, 2.3 to 2.8 kg), 2 monkeys inone group were used. A vehicle, 0.1 mg/body of the compound 33 or 1mg/body of the compound 33 was intravenously administered to themonkeys. 6 and 9 days after the administration, blood was collected byusing a blood-collecting tube EDTA-2K, and the numbers of bloodplatelets, white blood cells and red blood cells contained in theperipheral blood were measured by using an E-2500/cs. The results areshown in Tables 7-1, 7-2 and 7-3, respectively.

                  TABLE 7-1                                                       ______________________________________                                                          Number of Blood Platelets                                           dose      (× 10.sup.-4 /μl)                                  Compound  mg/body     after 6 days                                                                            after 9 days                                  ______________________________________                                        Vehicle   --          37.8 ± 8.5                                                                           37.4 ± 12.4                                33        0.1         56.4 ± 5.2                                                                           52.4 ± 9.0                                 33        1            62.1 ± 15.9                                                                         64.7 ± 23.7                                ______________________________________                                    

                  TABLE 7-2                                                       ______________________________________                                                          Number of White Blood Cells                                         dose      (× 10.sup.-2 /μl)                                  Compound  mg/body     after 6 days                                                                            after 9 days                                  ______________________________________                                        Vehicle   --           91 ± 31                                                                              94 ± 57                                   33        0.1         156 ± 1                                                                              105 ± 15                                   33        1           150 ± 37                                                                             169 ± 21                                   ______________________________________                                    

                  TABLE 7-3                                                       ______________________________________                                                          Number of Red Blood Cells                                           dose      (× 10.sup.-4 /μl)                                  Compound  mg/body     after 6 days                                                                            after 9 days                                  ______________________________________                                        Vehicle   --          516 ± 6                                                                              506 ± 1                                    33        0.1         498 ± 18                                                                             538 ± 2                                    33        1           569 ± 40                                                                             574 ± 37                                   ______________________________________                                    

As shown in Table 7-1, it was clearly proved that Compound 33 shows aremarkable blood-platelet-increasing effect even when administered at adose of 0.1 mg/body, which effect is almost equal to the effect obtainedwhen the compound is administered at a dose of lmg/body.

Further, as shown in Table 7-2, Compound 33 showed a remarkablewhite-blood-cell-increasing effect 6 days after the administration at adose of 0.1 mg/body, which effect was equal to the effect obtained whenthe compound was administered at a dose of 1 mg/body.

Furthermore, as shown in Table 7-3, a red-blood-cell-increasing effectwas clearly found, 9 days after the administration, in the groupadministered with 0.1 mg/body of Compound 33.

In addition, by the observation conducted until 10 days after theadministration, no abnormality in body weight and in general conditionwas found even in the group administered with 1 mg/body of Compound 33.

Preparation Example 1 (Injection)

    ______________________________________                                        (1) Compound of formula (A)                                                                           1 mg                                                  (2) Polysorbate        100 mg                                                 (3) Distilled water for injection                                                                    suitable amount                                        Total                   1 ml                                                  ______________________________________                                    

In accordance with the above formulation, (1) and (2) are dissolved in(3), and the solution is filtered through a sterilizer. The resultant isthen charged in a vial or an ampoule to give an injection.

Preparation Example 2 (Tablet)

    ______________________________________                                        (1) Compound of formula (A)                                                                            1 mg                                                 (2) Lactose              80 mg                                                (3) Corn starch          30 mg                                                (4) Hydroxypropylcellulose                                                                             3 mg                                                 (5) Magnesium stearate   1 mg                                                 Total                   115 mg                                                ______________________________________                                    

In accordance with the above formulation, (1) to (4) are admixed andgranulated to obtain granule to be used for preparing tablets. To thisgranule is added (5), and the mixture is made into a homogeneous powderwhich is subjected to compression molding by using a compressor to givetablets.

Test Examples!

Test Example 1: Cytotoxicity

100 μl/well of B16 mouse melanoma cells with a concentration of 1×10⁵cells/ml and 10 μl/well of one of Compounds 1 to 34 with a predeterminedconcentration were placed on a flat-bottomed 96 well microplate.Incubation was conducted under the conditions of 37° C. and 5% CO₂ for42 hours, and 0.5 μCi/well of ³ H-TdR was then added. After further 8hours, the cells were harvested, and the amount of ³ H-TdR taken in thecells was measured. It was found that all of the compounds had noinfluence upon cell proliferation even at the final concentration of 10μg/ml.

Test Example 2: Acute Toxicity

0.1, 1.0 or 10 mg/kg of Compound 5 or 33 was intravenously administeredto Crj:CD rats (male, 5 weeks old), 6 rats in one group. 7 days afterthe administration, a toxicity test was carried out.

As a result, it was found that the rats did not die even when thecompound was administered at a dose of 10 mg/kg. Moreover, noabnormality was found by a post-mortem examination. Therefore, the LD₅₀value is 10 mg/kg or more.

Industrial Applicability

The medicine of the present invention has extremely excellentcell-proliferation-accelerating effect, radioprotective effect,blood-platelet-increasing effect, and blood-platelet-decrease-inhibitoryeffect. It is therefore useful for accelerating marrow cellproliferation, for protecting human against radiation damage, and forthe treatment of thrombocytopenia.

What is claimed is:
 1. A method for treatment of damage to bone marrowcaused by radiation said radiation being gamma-ray or X-ray comprisingadministering to a human in need of such treatment an effctive amount ofan α-galactosylceramide selected from the group consisting of thefollowing compounds:(1)(2S,3R)-1-(α-D-galactopyransyloxy)-2-tetracosanoylamino-3-octadecanol,(2) (2S,3R)-2-docosanoylamino-1-(α-D-galactopyranosyloxy)-3-ectadecanol,(3) (2S,3R)-1-(α-D-galactopyranosyloxy)-2-icosanoylamino-3-octadecanol,(4)(2S,3R)-1-(α-D-galactopyranosyloxy)-2-octadecanoylamino-3-octadecanol,(5)(2S,3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-octadecanol,(6) (2S,3R)-1-(α-D-galactopyranosyloxy)-2-octanoylamino-3-octadecanol,(7)(2S3R)-1-(α-D-galactopyrarosyloxy)-2-tetracosanoylamino-3-tetradecanole(8)(2S3R)-1-(α-D-galactopyranosyloxy)-2-tetradecanoylamino-3-hexadecanol,(9) (2S,3R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-tetracosanoylamino!-3-octadecanol, (10)(2S,3S4R)-1-(α-D-galactopyranosyloxy(-2-tetracosanoyl-amino-3,4-octadecanediol,(11)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-heptadecanediol,(12)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-pentadecanediol,(13)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-undecanediol,(14),(2S,3S4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoyl-amino-3,4-heptadecanediol,(15) (2S,3S4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-tetracosanoylamino!-3,4-octadecanediol, (16)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-tetracosanoylamino!-3,4-heptadecanediol, (17)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-tetracosanoylamino!-3,4-pentadecanediol, (18)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-tetracosanoylamino!-3,4-undecanediol, (19)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-hexacosanoylamino!-3,4-octadecanediol, (20)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-hexacosanoylamino!-3,4-nonadecanediol, (21)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(R)-2-hydroxy-hexacosanoylamino!3-3,4-icosanediol, (22)(2,S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(S)-2-hydroxy-tetracosanoylamino!-3,4-haptadecanediol, (23)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-(S)-2-hydroxy-tetracosanoylamino!-16-methyl-3,4-heptadecanediol, (24)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-16-methyl-2-tetracosanoylamino-3,4-heptadecanediol,(25) (2S,3R)-1-(α-D-galactopyranosyloxy)-2-oleoylamino-3-octadecanol,(26)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoyl-amino-3,4-octadecanediol,and (27)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-octacosanoyl-amino-3,4-haptadecanediol.2. A method according to claim 1 whereim the α-galactosylceramide isselected from the group consisting of the following compounds:(1)(2S,3S,4R)-17-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-octadecanediol,(2) (2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-heptadecanediol,(3)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-pentadecanediol,(4)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-tetracosanoyl-amino-3,4-undecanediol,(5)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoyl-amino-3,4-heptadecanediol,(6)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-hexacosanoyl-amino-3,4-octadecanediol,and (7)(2S,3S,4R)-1-(α-D-galactopyranosyloxy)-2-octacosanoyl-amino-3,4-heptadecanediol.3. A method according to claim 2 wherein α-galactosylceramide is(2S,3S,4R)-1-(α-galactopyransyloxy)-2-hexacosanoylamino-3,4-octadecanediol.4. A method according to claim 1 wherein the radiation is X-ray.
 5. Amethod according to claim 2 wherein the radiation is X-ray.
 6. A methodaccording to claim 3 wherein the radiation is X-ray.
 7. A method fortreatment of damage to bone marrow caused by radiation said radiationbeing gamma-ray or X-ray comprising administering to a human in need ofsuch treatment an effective amount of an α-galactosylceramiderepresented by the following formula (II): ##STR30## wherein R₁represents --CH(OH)(CH₂)_(Y) CH₃ or --CH(OH)(CH₂)_(Y) CH(CH₃)₂ ; R₂represents H or OH; X is an integer of 18 to 26 and Y is an integer of 5to 17 with the proviso that when R₁ represents --CH(OH)(CH₂)_(Y) CH₃,and R₂ is H, X is an integer of 18 to 26 and Y is an integer of 5 to 15;when R₁ represents --CH(OH)(CH₂)_(Y) CH₃ R₂ is OH, X is an integer of 18to 26 and Y is an integer of 5 to 17; orwhen R₁ represents--CH(OH)(CH₂)_(Y) CH(CH₃)₂, R₂ is H, X is an integer of 20 to 24 and Yis an integer of 9 to
 13. 8. A method for treatment of damage to bonemarrow caused by radiation said radiation being gamma-ray or X-raycomprising administering to a human in need of such an effective amountof an α-galactosylceramide represented by the following formula (VII);##STR31## wherein X is an integer of 18 to 26, and Y is an integer of 5to
 15. 9. A method according to claim 8, wherein X in the formula (VII)is an integer of 21 to 25 and Y in the formula (VII) is an integer of 6to
 14. 10. A method for treatment of damage to bone marrow caused byradiation said radiation being gamma-ray or X-ray comprisingadministering to a human in need of such treatment an effective amountof an α-galactosylceramide represented by the following formula (VII):##STR32## wherein X is an integer of 18 to 26, and Y is an integer of 5to
 15. 11. A method according to claim 10, wherein X in the formula(VIII) is an integer of 21 to 25 and Y in the formula (VIII) is aninteger of 6 to
 14. 12. A method for treatment of damage to bone marrowcaused by radiation said radiation being gamma-ray or X-ray comrisingadministering to a human in need of such an effective amount of anα-galactosylceramide represented by the following formula (IX):##STR33## wherein X is an integer of 18 to 26, and Y is an integer of 5to
 17. 13. A method for treatment of damage to bone marrow caused byradiation said radiation being gamm-ray or X-ray comprisingadministering to a human in need of such an effective amount of anα-galactosylceramide represented by the following formula (XI):##STR34## wherein X is an integer of 20 to 24, and Y is an integer of 9to
 13. 14. A method for treatment of damage to bone marrow caused byradiation said radiation being gamma-ray or X-ray comprisingadministering to a human in need of such an effective amount of anα-galactosylceramide represented by the following formula (XIII):##STR35## wherein X is an integer of 20 to 24, and Y is an integer of 9to
 13. 15. A method according to claim 7 wherein the radiation is X-ray.16. A method according to claim 8 wherein the radiation is X-ray.
 17. Amethod according to claim 9 wherein the radiation ix X-ray.
 18. A methodaccording to claim 10 wherein the radiation is X-ray.
 19. A methodaccording to claim 11 wherein the radiation is X-ray.
 20. A methodaccording to claim 12 wherein the radiation is X-ray.
 21. A methodaccording to claim 13 wherein the radiation is X-ray.
 22. A methodaccording to claim 14 wherein the radiation is X-ray.